Challenges For Clinical Translation Research Articles

Sensitivity improved Cerenkov luminescence endoscopy using optimal system parameters.

The challenges of clinical translation of optical imaging, including the limited availability of clinically used imaging probes and the restricted penetration depth of light propagation in tissues can be avoided using Cerenkov luminescence endoscopy (CLE). However, the clinical applications of CLE are limited due to the low signal level of Cerenkov luminescence and the large transmission loss caused by the endoscope, which results in a relatively low detection sensitivity of current CLE. The aim of this study was to enhance the detection sensitivity of the CLE system and thus improve the system for clinical application in the detection of gastrointestinal diseases. Four optical fiber endoscopes were customized with different system parameters, including monofilament (MF) diameter of imaging fiber bundles, fiber material, probe coating, etc. The endoscopes were connected to the detector via a specifically designed straight connection device to form the CLE system. The β-2-[18F]-Fluoro-2-deoxy-D-glucose (18F-FDG) solution and the radionuclide of Gallium-68 (68Ga) were used to evaluate the performance of the CLE system. The images of the 18F-FDG solution acquired by the CLE were used to optimize imaging parameters of the system. By using the endoscope with optimized parameters, including the MF diameter of imaging fiber bundles, fiber materials, etc., the resolution and sensitivity of the assembled CLE system were measured by imaging the radionuclide of 68Ga. The results of 18F-FDG experiments showed that larger MF diameter led to higher collection efficiency. The fiber material and probe coating with high transmission ratios in the range of 400-900 nm also increased signal collection and transmission efficiency. The results of 68Ga evaluations showed that a minimum radioactive activity of radionuclides as low as 0.03 µCi was detected in vitro within 5 minutes, while that of 0.68 µCi can be detected within 1 minute. In vivo experiments also demonstrated that the developed CLE system achieved a high sensitivity at a submicrocurie level; that is, 0.44 µCi within 5 minutes, and 0.83 µCi within 1 minute. The weaker in vivo sensitivity was due to the attenuation of the signal by the mouse tissue skin and the autofluorescence interference produced by biological tissues. By optimizing the structural parameters of fiber endoscope and imaging parameters for data acquisition, we developed a CLE system with a sensitivity at submicrocurie level. These results support the possibility that this technology can clinically detect early tumors within 1 minute.

Amplifying antitumor T cell immunity with versatile drug delivery systems for personalized cancer immunotherapy

Cancer immunotherapy is becoming an important option for treating patients with cancer in clinic. Given the heterogeneity of tumors between individuals, personalized cancer immunotherapy is the most promising one. Tremendous progresses have been achieved to initialize personalized immunity in patients through delivering tumor-derived neoantigens or adoptive transfer of engineered immune cells such as T cells and nature killer cells. However, the objective response rate and therapeutic efficiency of most personalized immunotherapies are hampered by the biophysical barriers against drug delivery and the limited infiltration of engineered cells into solid tumors. To overcome these limitations, versatile drug delivery systems have been developed to deliver personalized tumor antigens to target and promote intratumoral infiltration of lymphocytes, thus generating a local immunogenic niche to induce potent and durable antitumor immune responses. In this review, we will summarize the major barriers for efficient personalized immunization, highlight our lab and several other groups’ efforts in versatile drug delivery systems for delivering tumor-specific antigens, autologous tumor cell-derived antigens and combining with adoptive transfer of engineered immune cells. At the end of this review, we also look forward to the future development of drug delivery system-based personalized immunotherapy and its challenges for clinical translation.

Current Limitations and Perspectives of Chimeric Antigen Receptor-T-Cells in Acute Myeloid Leukemia.

Simple SummaryAcute myeloid leukemia (AML) is the most frequent type of acute leukemia in adults. Allogeneic hematopoietic cell transplantation (allo-HCT) has been the only potentially curative treatment for the majority of patients. The ability of chimeric antigen receptor (CAR)-modified T-cell therapy directed against the CD19 antigen to induce durable remissions in patients with acute lymphoblastic leukemia (ALL) has provided optimism that this novel treatment paradigm can be extrapolated to AML. In this review, we provide an overview of candidate target antigens for CAR-T-cells in AML, an update on recent progress in preclinical and clinical development of investigational CAR-T-cell products, and discuss challenges for the clinical implementation of CAR-T-cell therapy in AML.Adoptive transfer of gene-engineered chimeric antigen receptor (CAR)-T-cells has emerged as a powerful immunotherapy for combating hematologic cancers. Several target antigens that are prevalently expressed on AML cells have undergone evaluation in preclinical CAR-T-cell testing. Attributes of an ‘ideal’ target antigen for CAR-T-cell therapy in AML include high-level expression on leukemic blasts and leukemic stem cells (LSCs), and absence on healthy tissues, normal hematopoietic stem and progenitor cells (HSPCs). In contrast to other blood cancer types, where CAR-T therapies are being similarly studied, only a rather small number of AML patients has received CAR-T-cell treatment in clinical trials, resulting in limited clinical experience for this therapeutic approach in AML. For curative AML treatment, abrogation of bulk blasts and LSCs is mandatory with the need for hematopoietic recovery after CAR-T administration. Herein, we provide a critical review of the current pipeline of candidate target antigens and corresponding CAR-T-cell products in AML, assess challenges for clinical translation and implementation in routine clinical practice, as well as perspectives for overcoming them.

Cell Membrane-Coated Mimics: A Methodological Approach for Fabrication, Characterization for Therapeutic Applications, and Challenges for Clinical Translation.

Cell membrane-coated (CMC) mimics are micro/nanosystems that combine an isolated cell membrane and a template of choice to mimic the functions of a cell. The design exploits its physicochemical and biological properties for therapeutic applications. The mimics demonstrate excellent biological compatibility, enhanced biointerfacing capabilities, physical, chemical, and biological tunability, ability to retain cellular properties, immune escape, prolonged circulation time, and protect the encapsulated drug from degradation and active targeting. These properties and the ease of adapting them for personalized clinical medicine have generated a significant research interest over the past decade. This review presents a detailed overview of the recent advances in the development of cell membrane-coated (CMC) mimics. The primary focus is to collate and discuss components, fabrication methodologies, and the significance of physiochemical and biological characterization techniques for validating a CMC mimic. We present a critical analysis of the two main components of CMC mimics: the template and the cell membrane and mapped their use in therapeutic scenarios. In addition, we have emphasized on the challenges associated with CMC mimics in their clinical translation. Overall, this review is an up to date toolbox that researchers can benefit from while designing and characterizing CMC mimics.

Overcoming TGFβ-mediated immune evasion in cancer.

Transforming growth factor-β (TGFβ) signalling controls multiple cell fate decisions during development and tissue homeostasis; hence, dysregulation of this pathway can drive several diseases, including cancer. Here we discuss the influence that TGFβ exerts on the composition and behaviour of different cell populations present in the tumour immune microenvironment, and the context-dependent functions of this cytokine in suppressing or promoting cancer. During homeostasis, TGFβ controls inflammatory responses triggered by exposure to the outside milieu in barrier tissues. Lack of TGFβ exacerbates inflammation, leading to tissue damage and cellular transformation. In contrast, as tumours progress, they leverage TGFβ to drive an unrestrained wound-healing programme in cancer-associated fibroblasts, as well as to suppress the adaptive immune system and the innate immune system. In consonance with this key role in reprogramming the tumour microenvironment, emerging data demonstrate that TGFβ-inhibitory therapies can restore cancer immunity. Indeed, this approach can synergize with other immunotherapies - including immune checkpoint blockade - to unleash robust antitumour immune responses in preclinical cancer models. Despite initial challenges in clinical translation, these findings have sparked the development of multiple therapeutic strategies that inhibit the TGFβ pathway, many of which are currently in clinical evaluation.

Modulating Sirtuin Biology and Nicotinamide Adenine Diphosphate Metabolism in Cardiovascular Disease-From Bench to Bedside.

Sirtuins (SIRT1–7) comprise a family of highly conserved deacetylases with distribution in different subcellular compartments. Sirtuins deacetylate target proteins depending on one common substrate, nicotinamide adenine diphosphate (NAD+), thus linking their activities to the status of cellular energy metabolism. Sirtuins had been linked to extending life span and confer beneficial effects in a wide array of immune-metabolic and cardiovascular diseases. SIRT1, SIRT3, and SIRT6 have been shown to provide protective effects in various cardiovascular disease models, by decreasing inflammation, improving metabolic profiles or scavenging oxidative stress. Sirtuins may be activated collectively by increasing their co-substrate NAD+. By supplementing NAD+ precursors, NAD+ boosters confer pan-sirtuin activation with protective cardiometabolic effects in the experimental setting: they improve endothelial dysfunction, protect from experimental heart failure, hypertension and decrease progression of liver steatosis. Different precursor molecules were applied ranging from nicotinamide (NAM), nicotinamide mononucleotide (NMN) to nicotinamide riboside (NR). Notably, not all experimental results showed protective effects. Moreover, the results are not as striking in clinical studies as in the controlled experimental setting. Species differences, (lack of) genetic heterogeneity, different metabolic pathways, dosing, administration routes and disease contexts may account for these challenges in clinical translation. At the clinical scale, caloric restriction can reduce the risks of cardiovascular disease and raise NAD+ concentration and sirtuin expression. In addition, antidiabetic drugs such as metformin or SGLT2 inhibitors may confer cardiovascular protection, indirectly via sirtuin activation. Overall, additional mechanistic insight and clinical studies are needed to better understand the beneficial effects of sirtuin activation and NAD+ boosters from bench to bedside.

Biofabrication Strategies for Musculoskeletal Disorders: Evolution towards Clinical Applications.

Biofabrication has emerged as an attractive strategy to personalise medical care and provide new treatments for common organ damage or diseases. While it has made impactful headway in e.g., skin grafting, drug testing and cancer research purposes, its application to treat musculoskeletal tissue disorders in a clinical setting remains scarce. Albeit with several in vitro breakthroughs over the past decade, standard musculoskeletal treatments are still limited to palliative care or surgical interventions with limited long-term effects and biological functionality. To better understand this lack of translation, it is important to study connections between basic science challenges and developments with translational hurdles and evolving frameworks for this fully disruptive technology that is biofabrication. This review paper thus looks closely at the processing stage of biofabrication, specifically at the bioinks suitable for musculoskeletal tissue fabrication and their trends of usage. This includes underlying composite bioink strategies to address the shortfalls of sole biomaterials. We also review recent advances made to overcome long-standing challenges in the field of biofabrication, namely bioprinting of low-viscosity bioinks, controlled delivery of growth factors, and the fabrication of spatially graded biological and structural scaffolds to help biofabricate more clinically relevant constructs. We further explore the clinical application of biofabricated musculoskeletal structures, regulatory pathways, and challenges for clinical translation, while identifying the opportunities that currently lie closest to clinical translation. In this article, we consider the next era of biofabrication and the overarching challenges that need to be addressed to reach clinical relevance.

Clinical translation of immunomodulatory therapeutics.

Immunomodulatory therapeutics represent a unique class of drug products that have tremendous potential to rebalance malfunctioning immune systems and are quickly becoming one of the fastest-growing areas in the pharmaceutical industry. For these drugs to become mainstream medicines, they must provide greater therapeutic benefit than the currently used treatments without causing severe toxicities. Immunomodulators, cell-based therapies, antibodies, and viral therapies have all achieved varying amounts of success in the treatment of cancers and/or autoimmune diseases. However, many challenges related to precision dosing, off-target effects, and manufacturing hurdles will need to be addressed before we see widespread adoption of these therapies in the clinic. This review provides a perspective on the progress of immunostimulatory and immunosuppressive therapies to date and discusses the opportunities and challenges for clinical translation of the next generation of immunomodulatory therapeutics.

Advances in Skin Tissue Bioengineering and the Challenges of Clinical Translation.

Skin tissue bioengineering is an emerging field that brings together interdisciplinary teams to promote successful translation to clinical care. Extensive deep tissue injuries, such as large burns and other major skin loss conditions, are medical indications where bioengineered skin substitutes (that restore both dermal and epidermal tissues) are being studied as alternatives. These may not only reduce mortality but also lessen morbidity to improve quality of life and functional outcome compared with the current standards of care. A common objective of dermal-epidermal therapies is to reduce the time required to accomplish stable closure of wounds with minimal scar in patients with insufficient donor sites for autologous split-thickness skin grafts. However, no commercially-available product has yet fully satisfied this objective. Tissue engineered skin may include cells, biopolymer scaffolds and drugs, and requires regulatory review to demonstrate safety and efficacy. They must be scalable for manufacturing and distribution. The advancement of technology and the introduction of bioreactors and bio-printing for skin tissue engineering may facilitate clinical products' availability. This mini-review elucidates the reasons for the few available commercial skin substitutes. In addition, it provides insights into the challenges faced by surgeons and scientists to develop new therapies and deliver the results of translational research to improve patient care.

In Vivo Cell Tracking Using PET: Opportunities and Challenges for Clinical Translation in Oncology.

Simple SummaryTracking therapeutic cells with non-invasive imaging methods has the potential to provide important information on the efficacy of cell therapies. In oncology, for example, monitoring the spatial distribution of chimeric antigen receptor (CAR) T-cells or tumour-infiltrating lymphocytes (TILs) could be used to monitor the efficiency of cellular trafficking to target sites within a patient. This review covers different cell labelling approaches for the non-invasive detection of therapeutic cells using positron emission tomography (PET). The potential for the clinical translation of these approaches and first-in-human studies is examined, as well as the translational challenges involved and how imaging can help overcome some of these challenges.Cell therapy is a rapidly evolving field involving a wide spectrum of therapeutic cells for personalised medicine in cancer. In vivo imaging and tracking of cells can provide useful information for improving the accuracy, efficacy, and safety of cell therapies. This review focuses on radiopharmaceuticals for the non-invasive detection and tracking of therapeutic cells using positron emission tomography (PET). A range of approaches for imaging therapeutic cells is discussed: Direct ex vivo labelling of cells, in vivo indirect labelling of cells by utilising gene reporters, and detection of specific antigens expressed on the target cells using antibody-based radiopharmaceuticals (immuno-PET). This review examines the evaluation of PET imaging methods for therapeutic cell tracking in preclinical cancer models, their role in the translation into patients, first-in-human studies, as well as the translational challenges involved and how they can be overcome.

Enabling Wearable Pulse Transit Time-Based Blood Pressure Estimation for Medically Underserved Areas and Health Equity: Comprehensive Evaluation Study.

BackgroundNoninvasive and cuffless approaches to monitor blood pressure (BP), in light of their convenience and accuracy, have paved the way toward remote screening and management of hypertension. However, existing noninvasive methodologies, which operate on mechanical, electrical, and optical sensing modalities, have not been thoroughly evaluated in demographically and racially diverse populations. Thus, the potential accuracy of these technologies in populations where they could have the greatest impact has not been sufficiently addressed. This presents challenges in clinical translation due to concerns about perpetuating existing health disparities.ObjectiveIn this paper, we aim to present findings on the feasibility of a cuffless, wrist-worn, pulse transit time (PTT)–based device for monitoring BP in a diverse population.MethodsWe recruited a diverse population through a collaborative effort with a nonprofit organization working with medically underserved areas in Georgia. We used our custom, multimodal, wrist-worn device to measure the PTT through seismocardiography, as the proximal timing reference, and photoplethysmography, as the distal timing reference. In addition, we created a novel data-driven beat-selection algorithm to reduce noise and improve the robustness of the method. We compared the wearable PTT measurements with those from a finger-cuff continuous BP device over the course of several perturbations used to modulate BP.ResultsOur PTT-based wrist-worn device accurately monitored diastolic blood pressure (DBP) and mean arterial pressure (MAP) in a diverse population (N=44 participants) with a mean absolute difference of 2.90 mm Hg and 3.39 mm Hg for DBP and MAP, respectively, after calibration. Meanwhile, the mean absolute difference of our systolic BP estimation was 5.36 mm Hg, a grade B classification based on the Institute for Electronics and Electrical Engineers standard. We have further demonstrated the ability of our device to capture the commonly observed demographic differences in underlying arterial stiffness.ConclusionsAccurate DBP and MAP estimation, along with grade B systolic BP estimation, using a convenient wearable device can empower users and facilitate remote BP monitoring in medically underserved areas, thus providing widespread hypertension screening and management for health equity.

Insights into an Immunotherapeutic Approach to Combat Multidrug Resistance in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has emerged as one of the most lethal cancers worldwide because of its high refractoriness and multi-drug resistance to existing chemotherapies, which leads to poor patient survival. Novel pharmacological strategies to tackle HCC are based on oral multi-kinase inhibitors like sorafenib; however, the clinical use of the drug is restricted due to the limited survival rate and significant side effects, suggesting the existence of a primary or/and acquired drug-resistance mechanism. Because of this hurdle, HCC patients are forced through incomplete therapy. Although multiple approaches have been employed in parallel to overcome multidrug resistance (MDR), the results are varying with insignificant outcomes. In the past decade, cancer immunotherapy has emerged as a breakthrough approach and has played a critical role in HCC treatment. The liver is the main immune organ of the lymphatic system. Researchers utilize immunotherapy because immune evasion is considered a major reason for rapid HCC progression. Moreover, the immune response can be augmented and sustained, thus preventing cancer relapse over the post-treatment period. In this review, we provide detailed insights into the immunotherapeutic approaches to combat MDR by focusing on HCC, together with challenges in clinical translation.

Recent Advances in Liposomal-Based Anti-Inflammatory Therapy.

Liposomes can be seen as ideal carriers for anti-inflammatory drugs as their ability to (passively) target sites of inflammation and release their content to inflammatory target cells enables them to increase local efficacy with only limited systemic exposure and adverse effects. Nonetheless, few liposomal formulations seem to reach the clinic. The current review provides an overview of the more recent innovations in liposomal treatment of rheumatoid arthritis, psoriasis, vascular inflammation, and transplantation. Cutting edge developments include the liposomal delivery of gene and RNA therapeutics and the use of hybrid systems where several liposomal bilayer features, or several drugs, are combined in a single formulation. The majority of the articles reviewed here focus on preclinical animal studies where proof-of-principle of an improved efficacy–safety ratio is observed when using liposomal formulations. A few clinical studies are included as well, which brings us to a discussion about the challenges of clinical translation of liposomal nanomedicines in the field of inflammatory diseases.

Inside Front Cover: Design of polymers for siRNA delivery: Recent progress and challenges (View 3/2021)

RNAi-mediated gene therapy is gradually becoming a conventional approach for the treatment of various diseases. One of the major challenges for clinical translation of RNAi is to efficiently deliver siRNA into targeted tissues and cells. Herein, in article number 20200026 Yiyun Cheng, Jia Lv and their co-workers have reviewed recent advances in the design of functional polymers to overcome the multiple extracellular and intracellular barriers during siRNA delivery in vitro and in vivo, and provided perspectives for future siRNA delivery systems.

JNK in Tumor Microenvironment: Present Findings and Challenges in Clinical Translation

Simple SummaryStress-activated c-Jun N-terminal kinases (JNKs) are members of mitogen-activated protein kinases (MAPKs). Apart from having both tumor promoting and tumor suppressing roles in cancers due to its impact on apoptosis and autophagy pathways, JNK also plays complex roles in the heterogeneous tumor microenvironment (TME) and is involved in different tumorigenesis pathways. The JNK pathway influences various stressful and chronic inflammatory conditions along with different cell populations in TME. In this review, we aim to present the current knowledge of JNK-mediated processes in TME and the challenges in clinical translation.The c-Jun N-terminal kinases (JNKs) are a group of mitogen-activated protein kinases (MAPKs). JNK is mainly activated under stressful conditions or by inflammatory cytokines and has multiple downstream targets for mediating cell proliferation, differentiation, survival, apoptosis, and immune responses. JNK has been demonstrated to have both tumor promoting and tumor suppressing roles in different cancers depending on the focused pathway in each study. JNK also plays complex roles in the heterogeneous tumor microenvironment (TME). JNK is involved in different tumorigenesis pathways. TME closely relates with tumor development and consists of various stressful and chronic inflammatory conditions along with different cell populations, in which the JNK pathway may have various mediating roles. In this review, we aim to summarize the present knowledge of JNK-mediated processes in TME, including hypoxia, reactive oxygen species, inflammation, immune responses, angiogenesis, as well as the regulation of various cell populations within TME. This review also suggests future research directions for translating JNK modulation in pre-clinical findings to clinical benefits.

NF-κB Blockade with Oral Administration of Dimethylaminoparthenolide (DMAPT), Delays Prostate Cancer Resistance to Androgen Receptor (AR) Inhibition and Inhibits AR Variants.

NF-κB activation has been linked to prostate cancer progression and is commonly observed in castrate-resistant disease. It has been suggested that NF-κB-driven resistance to androgen-deprivation therapy (ADT) in prostate cancer cells may be mediated by aberrant androgen receptor (AR) activation and AR splice variant production. Preventing resistance to ADT may therefore be achieved by using NF-κB inhibitors. However, low oral bioavailability and high toxicity of NF-κB inhibitors is a major challenge for clinical translation. Dimethylaminoparthenolide (DMAPT) is an oral NF-κB inhibitor in clinical development and has already shown favorable pharmacokinetic and pharmacodyanamic data in patients with heme malignancies, including decrease of NF-κB in circulating leuchemic blasts. Here, we report that activation of NF-κB/p65 by castration in mouse and human prostate cancer models resulted in a significant increase in AR variant-7 (AR-V7) expression and modest upregulation of AR. In vivo castration of VCaP-CR tumors resulted in significant upregulation of phosphorylated-p65 and AR-V7, which was attenuated by combination with DMAPT and DMAPT increased the efficacy of AR inhibition. We further demonstrate that the effects of DMAPT-sensitizing prostate cancer cells to castration were dependent on the ability of DMAPT to inhibit phosphorylated-p65 function. IMPLICATIONS: Our study shows that DMAPT, an oral NF-κB inhibitor in clinical development, inhibits phosphorylated-p65 upregulation of AR-V7 and delays prostate cancer castration resistance. This provides rationale for the development of DMAPT as a novel therapeutic strategy to increase durable response in patients receiving AR-targeted therapy.

Unresolved Issues in RNA Therapeutics in Vascular Diseases With a Focus on Aneurysm Disease.

New technologies have greatly shaped the scientific and medical landscape within the last years. The unprecedented expansion of data and information on RNA biology has led to the discovery of new RNA classes with unique functions and unexpected modifications. Today, the biggest challenge is to transfer the large number of findings in basic RNA biology into corresponding clinical RNA-based therapeutics. Lately, this research begins to yield positive outcomes. RNA drugs advance to the final phases of clinical trials or even receive FDA approval. Furthermore, the introduction of the RNA-guided gene-editing technology CRISPR and advances in the delivery of messenger RNAs have triggered a major progression in the field of RNA-therapeutics. Especially short interfering RNAs and antisense oligonucleotides are promising examples for novel categories of therapeutics. However, several issues need to be addressed including intracellular delivery, toxicity, and immune responses before utilizing RNAs in a clinical setting. In this review, we provide an overview on opportunities and challenges for clinical translation of RNA-based therapeutics, with an emphasis on advances in novel delivery technologies and abdominal aortic aneurysm disease where non-coding RNAs have been shown to play a crucial regulatory role.

CAR-T Cell Therapy for Acute Myeloid Leukemia: Preclinical Rationale, Current Clinical Progress, and Barriers to Success.

Chimeric antigen receptor (CAR)-T cell therapy has shown impressive results in chemorefractory B cell malignancies, raising the possibilities of using this immunotherapeutic modality for other devastating hematologic malignancies, such as acute myeloid leukemia (AML). AML is an aggressive hematologic malignancy which, like B cell malignancies, poses several challenges for clinical translation of successful immunotherapy. The antigenic heterogeneity of AML results in a list of potential targets that CAR-T cells could be directed towards, each with advantages and disadvantages. In this review, we provide an up-to-date report of outcomes and adverse effects from published and presented clinical trials of CAR-T cell therapy for AML and provide the preclinical rationale underlying these studies and antigen selection. Comparison across trials is difficult, yet themes emerge with respect to appropriate antigen selection and association of adverse effects with outcomes. We highlight currently active clinical trials and the potential improvements and caveats with these novel approaches. Key hurdles to the successful introduction of CAR-T cell therapy for the treatment of AML include the effect of antigenic heterogeneity and trade-offs between therapy specificity and sensitivity; on-target off-tumor toxicities; the AML tumor microenvironment; and practical considerations for future trials that should be addressed to enable successful CAR-T cell therapy for AML.

Pulmonary Functional Imaging: Part 1-State-of-the-Art Technical and Physiologic Underpinnings.

Over the past few decades, pulmonary imaging technologies have advanced from chest radiography and nuclear medicine methods to high-spatial-resolution or low-dose chest CT and MRI. It is currently possible to identify and measure pulmonary pathologic changes before these are obvious even to patients or depicted on conventional morphologic images. Here, key technological advances are described, including multiparametric CT image processing methods, inhaled hyperpolarized and fluorinated gas MRI, and four-dimensional free-breathing CT and MRI methods to measure regional ventilation, perfusion, gas exchange, and biomechanics. The basic anatomic and physiologic underpinnings of these pulmonary functional imaging techniques are explained. In addition, advances in image analysis and computational and artificial intelligence (machine learning) methods pertinent to functional lung imaging are discussed. The clinical applications of pulmonary functional imaging, including both the opportunities and challenges for clinical translation and deployment, will be discussed in part 2 of this review. Given the technical advances in these sophisticated imaging methods and the wealth of information they can provide, it is anticipated that pulmonary functional imaging will be increasingly used in the care of patients with lung disease. © RSNA, 2021 Online supplemental material is available for this article.

Dissecting the role of subiculum in epilepsy: Research update and translational potential.

The subiculum serves as the strategic core output of the hippocampus, through which neural activity exits the hippocampal proper and targets the entorhinal cortex and other more distant subcortical and cortical areas. The past decade has witnessed a growing interest in the subiculum, owing to discoveries revealing its critical role in regulating many physiological and pathophysiological processes. Notably, accumulating evidence from both clinical and experimental studies suggests that the subiculum plays a vital role in seizure initiation and propagation, in epilepsy. In this review, we briefly describe the structure and connectivity of the subiculum and then summarize the molecular and cellular mechanisms in the subiculum underlying the epileptic brain, in both epilepsy patients and animal models. Next, we review some translational approaches targeting the malfunctioned subiculum to treat epilepsy. Finally, we pose open questions for future research in the subiculum and their clinical translation challenges.