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Cells Oct 2023Immune checkpoint blockade (ICB) is a mainstay of treatment for advanced cancer, yet tumor response and host toxicity are heterogenous in those patients who receive ICB.... (Review)
Review
Immune checkpoint blockade (ICB) is a mainstay of treatment for advanced cancer, yet tumor response and host toxicity are heterogenous in those patients who receive ICB. There is growing interest in understanding how host factors interact with tumor intrinsic properties and the tumor microenvironment to influence the therapeutic index with ICB. Obesity, defined by body mass index, is a host factor associated with improved outcomes in select cancers when treated with ICB. While the biological mechanism for this obesity paradox is not fully understood, pre-clinical and translational studies suggest obesity may potentially impact tumor metabolism, inflammation, and angiogenesis. Herein, we summarize clinical studies that support an obesity paradox with ICB, explore potential biological mechanisms that may account for the obesity paradox, and address methodological challenges to consider when studying obesity and treatment outcomes.
Topics: Humans; Immune Checkpoint Inhibitors; Neoplasms; Obesity; Inflammation; Tumor Microenvironment
PubMed: 37947629
DOI: 10.3390/cells12212551 -
Understanding the spectrum of non-motor symptoms in multiple sclerosis: insights from animal models.Neural Regeneration Research Jan 2024Multiple sclerosis is a chronic autoimmune disease of the central nervous system and is generally considered to be a non-traumatic, physically debilitating neurological... (Review)
Review
Multiple sclerosis is a chronic autoimmune disease of the central nervous system and is generally considered to be a non-traumatic, physically debilitating neurological disorder. In addition to experiencing motor disability, patients with multiple sclerosis also experience a variety of non-motor symptoms, including cognitive deficits, anxiety, depression, sensory impairments, and pain. However, the pathogenesis and treatment of such non-motor symptoms in multiple sclerosis are still under research. Preclinical studies for multiple sclerosis benefit from the use of disease-appropriate animal models, including experimental autoimmune encephalomyelitis. Prior to understanding the pathophysiology and developing treatments for non-motor symptoms, it is critical to characterize the animal model in terms of its ability to replicate certain non-motor features of multiple sclerosis. As such, no single animal model can mimic the entire spectrum of symptoms. This review focuses on the non-motor symptoms that have been investigated in animal models of multiple sclerosis as well as possible underlying mechanisms. Further, we highlighted gaps in the literature to explain the non-motor aspects of multiple sclerosis in experimental animal models, which will serve as the basis for future studies.
PubMed: 37488849
DOI: 10.4103/1673-5374.375307 -
Physiological Reviews Apr 2024The last decade of microbiome research has highlighted its fundamental role in systemic immune and metabolic homeostasis. The microbiome plays a prominent role during... (Review)
Review
The last decade of microbiome research has highlighted its fundamental role in systemic immune and metabolic homeostasis. The microbiome plays a prominent role during gestation and into early life, when maternal lifestyle factors shape immune development of the newborn. Breast milk further shapes gut colonization, supporting the development of tolerance to commensal bacteria and harmless antigens while preventing outgrowth of pathogens. Environmental microbial and lifestyle factors that disrupt this process can dysregulate immune homeostasis, predisposing infants to atopic disease and childhood asthma. In health, the low-biomass lung microbiome, together with inhaled environmental microbial constituents, establishes the immunological set point that is necessary to maintain pulmonary immune defense. However, in disease perturbations to immunological and physiological processes allow the upper respiratory tract to act as a reservoir of pathogenic bacteria, which can colonize the diseased lung and cause severe inflammation. Studying these host-microbe interactions in respiratory diseases holds great promise to stratify patients for suitable treatment regimens and biomarker discovery to predict disease progression. Preclinical studies show that commensal gut microbes are in a constant flux of cell division and death, releasing microbial constituents, metabolic by-products, and vesicles that shape the immune system and can protect against respiratory diseases. The next major advances may come from testing and utilizing these microbial factors for clinical benefit and exploiting the predictive power of the microbiome by employing multiomics analysis approaches.
Topics: Infant, Newborn; Humans; Child; Lung; Microbiota; Asthma; Inflammation; Bacteria; Homeostasis
PubMed: 38059886
DOI: 10.1152/physrev.00020.2023 -
Journal of Experimental & Clinical... Sep 2023Our previous study first showed that ATR-binding long noncoding RNA (lncRNA) is necessary for ATR function and promotes cancer resistance. However, the specific lncRNAs...
BACKGROUND
Our previous study first showed that ATR-binding long noncoding RNA (lncRNA) is necessary for ATR function and promotes cancer resistance. However, the specific lncRNAs instrumental in ATR activation remain largely unclear, which limits our comprehensive understanding of this critical biological process.
METHODS
RNA immunoprecipitation (RIP) followed by RNA sequencing was employed to identify ATR-binding lncRNAs, which were further validated using RIP-qPCR assays. Immunofluorescence staining and Western blotting were applied to detect the activation of DNA damage repair factors. After the effect of scaRNA2 on cellular sensitivity to DNA-damaging reagents was determined, the effects of scaRNA2 on radiotherapy were investigated in patient-derived organoids and xenograft preclinical models. The clinical relevance of scaRNA2 was also validated in tissues isolated from rectal cancer patients.
RESULTS
ScaRNA2 was identified as the most enriched ATR-binding lncRNA and was found to be essential for homologous recombination (HR) mediated DNA damage repair. Furthermore, scaRNA2 knockdown abrogated the recruitment of ATR and its substrates in response to DNA damage. Mechanistically, scaRNA2 was observed to be necessary for Exo1-mediated DNA end resection and bridged the MRN complex to ATR activation. Knockdown of scaRNA2 effectively increased the sensitivity of cancer cells to multiple kinds of DNA damage-related chemoradiotherapy. Preclinically, knockdown of scaRNA2 improved the effects of radiotherapy on patient-derived organoids and xenograft models. Finally, an increase in scaRNA2 colocalized with ATR was also found in clinical patients who were resistant to radiotherapy.
CONCLUSIONS
ScaRNA2 was identified as the most abundant lncRNA bound to ATR and was demonstrated to bridge DNA end resection to ATR activation; thus, it could be applied as a potent target for combined cancer treatments with chemoradiotherapy.
Topics: Humans; Recombinational DNA Repair; RNA, Long Noncoding; DNA Repair; DNA Damage; DNA; Neoplasms; Ataxia Telangiectasia Mutated Proteins
PubMed: 37775817
DOI: 10.1186/s13046-023-02829-4 -
Nutritional Neuroscience Dec 2023Brain oxygen deprivation causes morphological damage involved in the formation of serious pathological conditions such as stroke and cerebral palsy. Therapeutic methods... (Review)
Review
Brain oxygen deprivation causes morphological damage involved in the formation of serious pathological conditions such as stroke and cerebral palsy. Therapeutic methods for post-hypoxia/anoxia injuries are limited and still have deficiencies in terms of safety and efficacy. Recently, clinical studies of stroke have reported the use of drugs containing riboflavin for post-injury clinical rehabilitation, however, the effects of vitamin B2 on exposure to cerebral oxygen deprivation are not completely elucidated. This review aimed to investigate the potential antioxidant, anti-inflammatory and neuroprotective effects of riboflavin in cerebral hypoxia/anoxia. After a systematic search, 21 articles were selected, 8 preclinical and 12 clinical studies, and 1 translational study. Most preclinical studies used B2 alone in models of hypoxia in rodents, with doses of 1-20 mg/kg (in vivo) and 0.5-5 µM (in vitro). Together, these works suggested greater regulation of lipid peroxidation and apoptosis and an increase in neurotrophins, locomotion, and cognition after treatment. In contrast, several human studies have administered riboflavin (5 mg) in combination with other Krebs cycle metabolites, except one study, which used only B2 (20 mg). A reduction in lactic acidosis and recovery of sensorimotor functions was observed in children after treatment with B2, while adults and the elderly showed a reduction in infarct volume and cognitive rehabilitation. Based on findings from preclinical and clinical studies, we conclude that the use of riboflavin alone or in combination acts beneficially in correcting the underlying brain damage caused by hypoxia/anoxia and its inflammatory, oxidative, and behavioral impairments.
PubMed: 38095869
DOI: 10.1080/1028415X.2023.2288387 -
Frontiers in Cellular Neuroscience 2023First theorized by Hebb, neuronal ensembles have provided a framework for understanding how the mammalian brain operates, especially regarding learning and memory.... (Review)
Review
First theorized by Hebb, neuronal ensembles have provided a framework for understanding how the mammalian brain operates, especially regarding learning and memory. Neuronal ensembles are discrete, sparsely distributed groups of neurons that become activated in response to a specific stimulus and are thought to provide an internal representation of the world. Beyond the study of region-wide or projection-wide activation, the study of ensembles offers increased specificity and resolution to identify and target specific memories or associations. Neuroscientists interested in the neurobiology of learning, memory, and motivated behavior have used electrophysiological-, calcium-, and protein-based proxies of neuronal activity in preclinical models to better understand the neurobiology of learned and motivated behaviors. Although these three approaches may be used to pursue the same general goal of studying neuronal ensembles, technical differences lead to inconsistencies in the output and interpretation of data. This mini-review highlights some of the methodologies used in electrophysiological-, calcium-, and protein-based studies of neuronal ensembles and discusses their strengths and weaknesses.
PubMed: 38155864
DOI: 10.3389/fncel.2023.1310724 -
Pediatric Research Apr 2024Similar to systematic reviews (SRs) in clinical fields, preclinical SRs address a specific research area, furnishing information on current knowledge, possible gaps, and... (Review)
Review
Similar to systematic reviews (SRs) in clinical fields, preclinical SRs address a specific research area, furnishing information on current knowledge, possible gaps, and potential methodological flaws of study design, conduct, and report. One of the main goals of preclinical SRs is to identify aspiring treatment strategies and evaluate if currently available data is solid enough to translate to clinical trials or highlight the gaps, thus justifying the need for new studies. It is imperative to rigorously follow the methodological standards that are widely available. These include registration of the protocol and adherence to guidelines for assessing the risk of bias, study quality, and certainty of evidence. A special consideration should be made for pediatric SRs, clinical and preclinical, due to the unique characteristics of this age group. These include rationale for intervention and comparison of primary and secondary outcomes. Outcomes measured should acknowledge age-related physiological changes and maturational processes of different organ systems. It is crucial to choose the age of the animals appropriately and its possible correspondence for specific pediatric age groups. The findings of well-conducted SRs of preclinical studies have the potential to provide a reliable evidence synthesis to guide the design of future preclinical and clinical studies. IMPACT: This narrative review highlights the importance of rigorous design, conduct and reporting of preclinical primary studies and systematic reviews. A special consideration should be made for pediatric systematic reviews of preclinical studies, due to the unique characteristics of this age group.
PubMed: 38615075
DOI: 10.1038/s41390-024-03197-1 -
European Urology Oncology Jun 2024Genomic studies have identified new subsets of aggressive prostate cancer (PCa) with poor prognosis (eg, neuroendocrine prostate cancer [NEPC], PCa with DNA damage...
BACKGROUND
Genomic studies have identified new subsets of aggressive prostate cancer (PCa) with poor prognosis (eg, neuroendocrine prostate cancer [NEPC], PCa with DNA damage response [DDR] alterations, or PCa resistant to androgen receptor pathway inhibitors [ARPIs]). Development of novel therapies relies on the availability of relevant preclinical models.
OBJECTIVE
To develop new preclinical models (patient-derived xenograft [PDX], PDX-derived organoid [PDXO], and patient-derived organoid [PDO]) representative of the most aggressive variants of PCa and to develop a new drug evaluation strategy.
DESIGN, SETTING, AND PARTICIPANTS
NEPC (n = 5), DDR (n = 7), and microsatellite instability (MSI)-high (n = 1) PDXs were established from 51 patients with metastatic PCa; PDXOs (n = 16) and PDOs (n = 6) were developed to perform drug screening. Histopathology and treatment response were characterized. Molecular profiling was performed by whole-exome sequencing (WES; n = 13), RNA sequencing (RNA-seq; n = 13), and single-cell RNA-seq (n = 14). WES and RNA-seq data from patient tumors were compared with the models.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Relationships with outcome were analyzed using the multivariable chi-square test and the tumor growth inhibition test.
RESULTS AND LIMITATIONS
Our PDXs captured both common and rare molecular phenotypes and their molecular drivers, including alterations of BRCA2, CDK12, MSI-high status, and NEPC. RNA-seq profiling demonstrated broad representation of PCa subtypes. Single-cell RNA-seq indicates that PDXs reproduce cellular and molecular intratumor heterogeneity. WES of matched patient tumors showed preservation of most genetic driver alterations. PDXOs and PDOs preserve drug sensitivity of the matched tissue and can be used to determine drug sensitivity.
CONCLUSIONS
Our models reproduce the phenotypic and genomic features of both common and aggressive PCa variants and capture their molecular heterogeneity. Successfully developed aggressive-variant PCa preclinical models provide an important tool for predicting tumor response to anticancer therapy and studying resistance mechanisms.
PATIENT SUMMARY
In this report, we looked at the outcomes of preclinical models from patients with metastatic prostate cancer enrolled in the MATCH-R trial (NCT02517892).
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Animals; Mice; Xenograft Model Antitumor Assays; Disease Models, Animal
PubMed: 38433714
DOI: 10.1016/j.euo.2023.10.011 -
Current Protocols Mar 2024Human sepsis is a complex disease that manifests with a diverse range of phenotypes and inherent variability among individuals, making it hard to develop a comprehensive...
Human sepsis is a complex disease that manifests with a diverse range of phenotypes and inherent variability among individuals, making it hard to develop a comprehensive animal model. Despite this difficulty, numerous models have been developed that capture many key aspects of human sepsis. The robustness of these models is vital for conducting pre-clinical studies to test and develop potential therapeutics. In this article, we describe four different models of murine sepsis that can be used to address different scientific questions relevant to the pathology and immune response during and after a septic event. Basic Protocol 1 details a non-synchronous cecal ligation and puncture (CLP) model of sepsis, where mice are subjected to polymicrobial exposure through surgery at different time points within 2 weeks. This variation in sepsis onset establishes each mouse at a different state of inflammation and cytokine levels that mimics the variability observed in humans when they present in the clinic. This model is ideal for studying the long-term impact of sepsis on the host. Basic Protocol 2 is also a type of polymicrobial sepsis, where injection of a specific amount of cecal slurry from a donor mouse into the peritoneum of recipient mice establishes immediate inflammation and sepsis without any need for surgery. Basic Protocol 3 describes infecting mice with a defined gram-positive or -negative bacterial strain to model a subset of sepsis observed in humans infected with a single pathogen. Basic Protocol 4 describes administering LPS to induce sterile endotoxemia. This form of sepsis is observed in humans exposed to bacterial toxins from the environment. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Non-synchronous cecal ligation and puncture Basic Protocol 2: Cecal slurry model of murine sepsis Basic Protocol 3: Monomicrobial model of murine sepsis Basic Protocol 4: LPS model of murine sepsis.
Topics: Humans; Animals; Mice; Lipopolysaccharides; Disease Models, Animal; Sepsis; Ambulatory Care Facilities; Inflammation
PubMed: 38439603
DOI: 10.1002/cpz1.997 -
European Journal of Clinical... Jul 2024Brain-derived neurotrophic factor (BDNF) dysfunction is one of the most important mechanisms underlying depression. It seems that selective serotonin reuptake inhibitors... (Comparative Study)
Comparative Study Review
Brain-derived neurotrophic factor (BDNF) dysfunction is one of the most important mechanisms underlying depression. It seems that selective serotonin reuptake inhibitors (SSRIs) improve depression via affecting BDNF level. In this systematic review, for the first time, we aimed to review the effect of three SSRIs including fluoxetine, escitalopram, and sertraline, on both depression and BDNF level in preclinical and clinical studies. PubMed electronic database was searched, and 193 articles were included in this study. After reviewing all manuscripts, only one important difference was found: subjects. We found that SSRIs induce different effects in animals vs. humans. Preclinical studies showed many controversial effects, while human studies showed only two effects: improvement of depression, with or without the improvement of BDNF. However, most studies used chronic SSRIs treatment, while acute SSRIs were not effectively used and evaluated. In conclusion, it seems that SSRIs are reliable antidepressants, and the improvement effect of SSRIs on depression is not dependent to BDNF level (at least in human studies).
Topics: Humans; Brain-Derived Neurotrophic Factor; Sertraline; Selective Serotonin Reuptake Inhibitors; Fluoxetine; Animals; Depression; Escitalopram; Antidepressive Agents
PubMed: 38558317
DOI: 10.1007/s00228-024-03680-y