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Journal of the American Society of... Mar 2022Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and... (Review)
Review
Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and regenerative processes. However, during AKI, the transition of AKI to CKD, sepsis-associated AKI, and kidney transplantation ferroptosis and necroptosis, two pathways associated with the loss of plasma membrane integrity, kill renal cells. This necrotic type of cell death is associated with an inflammatory response, which is referred to as necroinflammation. Importantly, the necroinflammatory response to cells that die by necroptosis may be fundamentally different from the tissue response to ferroptosis. Although mechanisms of ferroptosis and necroptosis have recently been investigated in detail, the cell death propagation during tubular necrosis, although described morphologically, remains incompletely understood. Here, we argue that a molecular switch downstream of tubular necrosis determines nephron regeneration versus nephron loss. Unraveling the details of this "switch" must include the inflammatory response to tubular necrosis and regenerative signals potentially controlled by inflammatory cells, including the stimulation of myofibroblasts as the origin of fibrosis. Understanding in detail the molecular switch and the inflammatory responses to tubular necrosis can inform the discussion of therapeutic options.
Topics: Acute Kidney Injury; Apoptosis; Female; Humans; Kidney; Kidney Cortex Necrosis; Male; Necrosis; Nephrons; Renal Insufficiency, Chronic
PubMed: 35022311
DOI: 10.1681/ASN.2021101293 -
Frontiers in Oncology 2022In recent years, various systemic immunotherapies have been developed for cancer treatment, such as monoclonal antibodies (mABs) directed against immune checkpoints... (Review)
Review
In recent years, various systemic immunotherapies have been developed for cancer treatment, such as monoclonal antibodies (mABs) directed against immune checkpoints (immune checkpoint inhibitors, ICIs), oncolytic viruses, cytokines, cancer vaccines, and adoptive cell transfer. While being estimated to be eligible in 38.5% of patients with metastatic solid or hematological tumors, ICIs, in particular, demonstrate durable disease control across many oncologic diseases (e.g., in melanoma, lung, bladder, renal, head, and neck cancers) and overall survival benefits. Due to their unique mechanisms of action based on T-cell activation, response to immunotherapies is characterized by different patterns, such as progression prior to treatment response (pseudoprogression), hyperprogression, and dissociated responses following treatment. Because these features are not encountered in the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), which is the standard for response assessment in oncology, new criteria were defined for immunotherapies. The most important changes in these new morphologic criteria are, firstly, the requirement for confirmatory imaging examinations in case of progression, and secondly, the appearance of new lesions is not necessarily considered a progressive disease. Until today, five morphologic (immune-related response criteria (irRC), immune-related RECIST (irRECIST), immune RECIST (iRECIST), immune-modified RECIST (imRECIST), and intra-tumoral RECIST (itRECIST)) criteria have been developed to accurately assess changes in target lesion sizes, taking into account the specific response patterns after immunotherapy. In addition to morphologic response criteria, 2-deoxy-2-[F]fluoro-D-glucose positron emission tomography/computed tomography (F-FDG-PET/CT) is a promising option for metabolic response assessment and four metabolic criteria are used (PET/CT Criteria for Early Prediction of Response to Immune Checkpoint Inhibitor Therapy (PECRIT), PET Response Evaluation Criteria for Immunotherapy (PERCIMT), immunotherapy-modified PET Response Criteria in Solid Tumors (imPERCIST5), and immune PERCIST (iPERCIST)). Besides, there is evidence that parameters on F-FDG-PET/CT, such as the standardized uptake value (SUV)max and several radiotracers, e.g., directed against PD-L1, may be potential imaging biomarkers of response. Moreover, the emerge of human intratumoral immunotherapy (HIT-IT), characterized by the direct injection of immunostimulatory agents into a tumor lesion, has given new importance to imaging assessment. This article reviews the specific imaging patterns of tumor response and progression and available imaging response criteria following immunotherapy.
PubMed: 36387133
DOI: 10.3389/fonc.2022.982983 -
Nano Letters Mar 2018Various delivery vectors have been integrated within biologically derived membrane systems to extend their residential time and reduce their reticuloendothelial system...
Various delivery vectors have been integrated within biologically derived membrane systems to extend their residential time and reduce their reticuloendothelial system (RES) clearance during systemic circulation. However, rational design is still needed to further improve the in situ penetration efficiency of chemo-drug-loaded membrane delivery-system formulations and their release profiles at the tumor site. Here, a macrophage-membrane-coated nanoparticle is developed for tumor-targeted chemotherapy delivery with a controlled release profile in response to tumor microenvironment stimuli. Upon fulfilling its mission of tumor homing and RES evasion, the macrophage-membrane coating can be shed via morphological changes driven by extracellular microenvironment stimuli. The nanoparticles discharged from the outer membrane coating show penetration efficiency enhanced by their size advantage and surface modifications. After internalization by the tumor cells, the loaded drug is quickly released from the nanoparticles in response to the endosome pH. The designed macrophage-membrane-coated nanoparticle (cskc-PPiP/PTX@Ma) exhibits an enhanced therapeutic effect inherited from both membrane-derived tumor homing and step-by-step controlled drug release. Thus, the combination of a biomimetic cell membrane and a cascade-responsive polymeric nanoparticle embodies an effective drug delivery system tailored to the tumor microenvironment.
Topics: Animals; Antineoplastic Agents, Phytogenic; Biomimetic Materials; Breast Neoplasms; Cell Line, Tumor; Cell Membrane; Delayed-Action Preparations; Drug Delivery Systems; Female; Humans; Macrophages; Mice; Nanoparticles; Paclitaxel; Tumor Microenvironment
PubMed: 29473753
DOI: 10.1021/acs.nanolett.7b05263 -
Eye (London, England) Jun 2015The introduction of anti-vascular endothelial growth factor (anti-VEGF) has made significant impact on the reduction of the visual loss due to neovascular age-related... (Review)
Review
The introduction of anti-vascular endothelial growth factor (anti-VEGF) has made significant impact on the reduction of the visual loss due to neovascular age-related macular degeneration (n-AMD). There are significant inter-individual differences in response to an anti-VEGF agent, made more complex by the availability of multiple anti-VEGF agents with different molecular configurations. The response to anti-VEGF therapy have been found to be dependent on a variety of factors including patient's age, lesion characteristics, lesion duration, baseline visual acuity (VA) and the presence of particular genotype risk alleles. Furthermore, a proportion of eyes with n-AMD show a decline in acuity or morphology, despite therapy or require very frequent re-treatment. There is currently no consensus as to how to classify optimal response, or lack of it, with these therapies. There is, in particular, confusion over terms such as 'responder status' after treatment for n-AMD, 'tachyphylaxis' and 'recalcitrant' n-AMD. This document aims to provide a consensus on definition/categorisation of the response of n-AMD to anti-VEGF therapies and on the time points at which response to treatment should be determined. Primary response is best determined at 1 month following the last initiation dose, while maintained treatment (secondary) response is determined any time after the 4th visit. In a particular eye, secondary responses do not mirror and cannot be predicted from that in the primary phase. Morphological and functional responses to anti-VEGF treatments, do not necessarily correlate, and may be dissociated in an individual eye. Furthermore, there is a ceiling effect that can negate the currently used functional metrics such as >5 letters improvement when the baseline VA is good (ETDRS>70 letters). It is therefore important to use a combination of both the parameters in determining the response.The following are proposed definitions: optimal (good) response is defined as when there is resolution of fluid (intraretinal fluid; IRF, subretinal fluid; SRF and retinal thickening), and/or improvement of >5 letters, subject to the ceiling effect of good starting VA. Poor response is defined as <25% reduction from the baseline in the central retinal thickness (CRT), with persistent or new IRF, SRF or minimal or change in VA (that is, change in VA of 0+4 letters). Non-response is defined as an increase in fluid (IRF, SRF and CRT), or increasing haemorrhage compared with the baseline and/or loss of >5 letters compared with the baseline or best corrected vision subsequently. Poor or non-response to anti-VEGF may be due to clinical factors including suboptimal dosing than that required by a particular patient, increased dosing intervals, treatment initiation when disease is already at an advanced or chronic stage), cellular mechanisms, lesion type, genetic variation and potential tachyphylaxis); non-clinical factors including poor access to clinics or delayed appointments may also result in poor treatment outcomes. In eyes classified as good responders, treatment should be continued with the same agent when disease activity is present or reactivation occurs following temporary dose holding. In eyes that show partial response, treatment may be continued, although re-evaluation with further imaging may be required to exclude confounding factors. Where there is persistent, unchanging accumulated fluid following three consecutive injections at monthly intervals, treatment may be withheld temporarily, but recommenced with the same or alternative anti-VEGF if the fluid subsequently increases (lesion considered active). Poor or non-response to anti-VEGF treatments requires re-evaluation of diagnosis and if necessary switch to alternative therapies including other anti-VEGF agents and/or with photodynamic therapy (PDT). Idiopathic polypoidal choroidopathy may require treatment with PDT monotherapy or combination with anti-VEGF. A committee comprised of retinal specialists with experience of managing patients with n-AMD similar to that which developed the Royal College of Ophthalmologists Guidelines to Ranibizumab was assembled. Individual aspects of the guidelines were proposed by the committee lead (WMA) based on relevant reference to published evidence base following a search of Medline and circulated to all committee members for discussion before approval or modification. Each draft was modified according to feedback from committee members until unanimous approval was obtained in the final draft. A system for categorising the range of responsiveness of n-AMD lesions to anti-VEGF therapy is proposed. The proposal is based primarily on morphological criteria but functional criteria have been included. Recommendations have been made on when to consider discontinuation of therapy either because of success or futility. These guidelines should help clinical decision-making and may prevent over and/or undertreatment with anti-VEGF therapy.
Topics: Angiogenesis Inhibitors; Humans; Intravitreal Injections; Practice Guidelines as Topic; Treatment Outcome; Vascular Endothelial Growth Factor A; Visual Acuity; Wet Macular Degeneration
PubMed: 25882328
DOI: 10.1038/eye.2015.48 -
Cell Mar 2024Dorsal root ganglia (DRG) somatosensory neurons detect mechanical, thermal, and chemical stimuli acting on the body. Achieving a holistic view of how different DRG...
Dorsal root ganglia (DRG) somatosensory neurons detect mechanical, thermal, and chemical stimuli acting on the body. Achieving a holistic view of how different DRG neuron subtypes relay neural signals from the periphery to the CNS has been challenging with existing tools. Here, we develop and curate a mouse genetic toolkit that allows for interrogating the properties and functions of distinct cutaneous targeting DRG neuron subtypes. These tools have enabled a broad morphological analysis, which revealed distinct cutaneous axon arborization areas and branching patterns of the transcriptionally distinct DRG neuron subtypes. Moreover, in vivo physiological analysis revealed that each subtype has a distinct threshold and range of responses to mechanical and/or thermal stimuli. These findings support a model in which morphologically and physiologically distinct cutaneous DRG sensory neuron subtypes tile mechanical and thermal stimulus space to collectively encode a wide range of natural stimuli.
Topics: Animals; Mice; Ganglia, Spinal; Sensory Receptor Cells; Single-Cell Gene Expression Analysis; Skin
PubMed: 38442711
DOI: 10.1016/j.cell.2024.02.006 -
Sports Medicine - Open Dec 2015The present article systematically reviews recent literature on the in vivo adaptation of asymptomatic human tendons following increased chronic mechanical loading, and... (Review)
Review
BACKGROUND
The present article systematically reviews recent literature on the in vivo adaptation of asymptomatic human tendons following increased chronic mechanical loading, and meta-analyzes the loading conditions, intervention outcomes, as well as methodological aspects.
METHODS
The search was performed in the databases PubMed, Web of Knowledge, and Scopus as well as in the reference lists of the eligible articles. A study was included if it conducted (a) a longitudinal exercise intervention (≥8 weeks) on (b) healthy humans (18 to 50 years), (c) investigating the effects on mechanical (i.e., stiffness), material (i.e., Young's modulus) and/or morphological properties (i.e., cross-sectional area (CSA)) of tendons in vivo, and was reported (d) in English language. Weighted average effect sizes (SMD, random-effects) and heterogeneity (Q and I statistics) of the intervention-induced changes of tendon stiffness, Young's modulus, and CSA were calculated. A subgroup analysis was conducted regarding the applied loading intensity, muscle contraction type, and intervention duration. Further, the methodological study quality and the risk of bias were assessed.
RESULTS
The review process yielded 27 studies with 37 separate interventions on either the Achilles or patellar tendon (264 participants). SMD was 0.70 (confidence interval: 0.51, 0.88) for tendon stiffness (N=37), 0.69 (0.36, 1.03) for Young's modulus (N=17), and 0.24 (0.07, 0.42) for CSA (N=33), with significant overall intervention effects (p<0.05). The heterogeneity analysis (stiffness: I =30%; Young's modulus: I =57%; CSA: I =21%) indicated that differences in the loading conditions may affect the adaptive responses. The subgroup analysis confirmed that stiffness adaptation significantly (p<0.05) depends on loading intensity (I =0%), but not on muscle contraction type. Although not significantly different, SMD was higher for interventions with longer duration (≥12 weeks). The average score of 71±9% in methodological quality assessment indicated an appropriate quality of most studies.
CONCLUSIONS
The present meta-analysis provides elaborate statistical evidence that tendons are highly responsive to diverse loading regimens. However, the data strongly suggests that loading magnitude in particular plays a key role for tendon adaptation in contrast to muscle contraction type. Furthermore, intervention-induced changes in tendon stiffness seem to be more attributed to adaptations of the material rather than morphological properties.
PubMed: 27747846
DOI: 10.1186/s40798-015-0009-9 -
BioRxiv : the Preprint Server For... Apr 2023Mechanical and thermal stimuli acting on the skin are detected by morphologically and physiologically distinct sensory neurons of the dorsal root ganglia (DRG)....
Mechanical and thermal stimuli acting on the skin are detected by morphologically and physiologically distinct sensory neurons of the dorsal root ganglia (DRG). Achieving a holistic view of how this diverse neuronal population relays sensory information from the skin to the central nervous system (CNS) has been challenging with existing tools. Here, we used transcriptomic datasets of the mouse DRG to guide development and curation of a genetic toolkit to interrogate transcriptionally defined DRG neuron subtypes. Morphological analysis revealed unique cutaneous axon arborization areas and branching patterns of each subtype. Physiological analysis showed that subtypes exhibit distinct thresholds and ranges of responses to mechanical and/or thermal stimuli. The somatosensory neuron toolbox thus enables comprehensive phenotyping of most principal sensory neuron subtypes. Moreover, our findings support a population coding scheme in which the activation thresholds of morphologically and physiologically distinct cutaneous DRG neuron subtypes tile multiple dimensions of stimulus space.
PubMed: 37131664
DOI: 10.1101/2023.04.22.537932 -
Science Advances May 2022The healthy functioning of the plants' vasculature depends on their ability to respond to environmental changes. In contrast, synthetic microfluidic systems have rarely...
The healthy functioning of the plants' vasculature depends on their ability to respond to environmental changes. In contrast, synthetic microfluidic systems have rarely demonstrated this environmental responsiveness. Plants respond to environmental stimuli through nastic movement, which inspires us to introduce transformable microfluidics: By embedding stimuli-responsive materials, the microfluidic device can respond to temperature, humidity, and light irradiance. Furthermore, by designing a foldable geometry, these responsive movements can follow the preset origami transformation. We term this device TransfOrigami microfluidics (TOM) to highlight the close connection between its transformation and the origami structure. TOM can be used as an environmentally adaptive photomicroreactor. It senses the environmental stimuli and feeds them back positively into photosynthetic conversion through morphological transformation. The principle behind this morphable microsystem can potentially be extended to applications that require responsiveness between the environment and the devices, such as dynamic artificial vascular networks and shape-adaptive flexible electronics.
PubMed: 35507654
DOI: 10.1126/sciadv.abo1719 -
International Journal of Molecular... Nov 2021Drought stress causes changes in the morphological, physiological, biochemical and molecular characteristics of plants. The response to drought in different plants may... (Review)
Review
Drought stress causes changes in the morphological, physiological, biochemical and molecular characteristics of plants. The response to drought in different plants may vary from avoidance, tolerance and escape to recovery from stress. This response is genetically programmed and regulated in a very complex yet synchronized manner. The crucial genetic regulations mediated by non-coding RNAs (ncRNAs) have emerged as game-changers in modulating the plant responses to drought and other abiotic stresses. The ncRNAs interact with their targets to form potentially subtle regulatory networks that control multiple genes to determine the overall response of plants. Many long and small drought-responsive ncRNAs have been identified and characterized in different plant varieties. The miRNA-based research is better documented, while lncRNA and transposon-derived RNAs are relatively new, and their cellular role is beginning to be understood. In this review, we have compiled the information on the categorization of non-coding RNAs based on their biogenesis and function. We also discuss the available literature on the role of long and small non-coding RNAs in mitigating drought stress in plants.
Topics: Droughts; Gene Expression Regulation, Plant; MicroRNAs; Plant Development; Plants; RNA, Long Noncoding; RNA, Untranslated; Stress, Physiological
PubMed: 34830399
DOI: 10.3390/ijms222212519 -
Cancers Jan 2022Hepatocellular carcinoma (HCC) is the third highest cause of cancer-related mortality, and liver transplantation is the ideal treatment for this disease. The Milan... (Review)
Review
Hepatocellular carcinoma (HCC) is the third highest cause of cancer-related mortality, and liver transplantation is the ideal treatment for this disease. The Milan criteria provided the opportunity for HCC patients to undergo LT with favorable outcomes and have been the international gold standard and benchmark. With the accumulation of data, however, the Milan criteria are not regarded as too restrictive. After the implementation of the Milan criteria, many extended criteria have been proposed, which increases the limitations regarding the morphological tumor burden, and incorporates the tumor's biological behavior using surrogate markers. The paradigm for the patient selection for LT appears to be shifting from morphologic criteria to a combination of biologic, histologic, and morphologic criteria, and to the establishment of a model for predicting post-transplant recurrence and outcomes. This review article aims to characterize the various patient selection criteria for LT, with reference to several surrogate markers for the biological behavior of HCC (e.g., AFP, PIVKA-II, NLR, 18F-FDG PET/CT, liquid biopsy), and the response to locoregional therapy. Furthermore, the allocation rules in each country and the present evidence on the role of down-staging large tumors are addressed.
PubMed: 35053580
DOI: 10.3390/cancers14020419