Publications

PURPOSE: This study aims to evaluate the cumulative equivalent dose in 2 Gy fractions (EQD2) to organs at risk and its potential correlation with toxicities in patients with locally advanced nonsmall cell lung cancer treated with very high mediastinal radiation therapy doses using mixed fractionation.

METHODS AND MATERIALS: Patients from a previously reported phase 1 trial (PMID: 29650404) were included (n = 26). They received a stereotactic boost (3 × 7-12 Gy) following chemoradiation therapy (cisplatin-based chemotherapy and 23 × 2 Gy using three-dimensional conformal radiation therapy). Seventeen treatment plans were available for dosimetric analysis. Doses delivered at each point of the planning computed tomography scan from each treatment phase were converted to EQD2 based on the α:β ratios, which are shown in asterisks following each converted dose. The 3-dimensional conformal radiation therapy and stereotactic body radiation therapy plans were each converted to EQD2, and their summation was used to estimate the total dose delivered to organs at risk.

RESULTS: In the entire cohort (n = 26), 77% of tumors were ultracentral, 19% peripheral, and 4% central. We observed 1 grade 3 toxicity (bronchial stenosis/fibrosis), 1 grade 4 toxicity (esophagitis with fistula), and 1 grade 5 toxicity (fatal hemoptysis). Dosimetric evaluation of the proximal bronchovascular (PBV) tree and esophagus revealed no severe late toxicity with PBV tree D1cc < 150 Gy *2* and esophageal D1cc < 100 Gy *10*. Median maximal EQD2 D1cc for organs at risk were as follows: aorta, 84.3 Gy *3* (range, 53.3-190.6); pulmonary arteries, 136.9 Gy *3* (range, 47.2-232.3); superior vena cava, 70.6 Gy *3* (range, 16.2-192.8); pulmonary veins, 69.0 Gy *3* (range, 3.5-231); esophagus, 67.9 Gy *10* (range, 15.7-161); PBV tree, 153.4 Gy *2* (range, 20.3-235.9).

CONCLUSIONS: The following preliminary dose constraints-PBV tree D1cc < 150 Gy *2* and esophageal D1cc < 100 Gy *10*-may be safe and are currently being prospectively evaluated in an ongoing phase 2 trial (NCT06627738). The correlation between toxicities and the degree of initial tumor infiltration of organs at risk requires further prospective evaluation.

Viruses and other microorganisms are constantly mutating and emerging in different regions. Here, we apply nanotechnology to examine the primary, secondary, and tertiary structures of novel noncoding RNA nanoparticles and find that primary sequences (1D) vary widely between viruses, while secondary (2D) and tertiary structures (3D) are highly conserved. The uniqueness of the phi29 system makes this reported study possible. RNA evolution studies are relevant to the concept of RNA as the origin of life. The recent discovery that RNA is a motile and recombinant entity supports the hypothesis that RNA is the substance of life. Previously, we reported noncoding RNA nanoparticles packaging RNA (pRNA) of the Bacillus virus phi29 (Nature Nanotechnology, 2011, PMID: 21909084; Nature Nanotechnology, 2010, PMID: 21102465; Science, 1987, PMID: 3107124). Phi29 can infect spore-forming Bacillus subtilis, which has long been hidden in the soil with slow or no evolution due to the protection of spores. They are living fossils. The pRNA of the phi29 DNA packaging motor drives the viral motor for DNA transport. In this study, we used existing datasets to search for more pRNAs. Their primary sequence diversity makes it challenging to identify them from the whole genomes of other species. Using the top-down (1D) approach and the bottom-up assembly (3D) approaches, we found that their 2D and 3D structures are highly conserved. Structural conservation enabled us to apply the two-dimensional structure-based approach to find these ncRNAs from databases and identify 12 new pRNAs. The presence of two additional components in the genome, a motor channel protein and a motor ATPase, further confirmed the authenticity of these pRNAs and supported the conclusion that these pRNAs are motor-driven components. Highly conserved and paired left and right loops for assembling the pRNA hexamer were identified in all 12 pRNAs. Artificial modification of the pairing and determination of the virion production activity of the mutated phi29 pRNA further confirmed the conclusion that the secondary and tertiary structures are highly conserved. Understanding the retention, conservation, and variation of viral non-coding RNA sequences and structure can help us trace the evolutionary history of the virus, find lineage information, and provide important information about the origin of the viruses. It can also provide knowledge for the design of disease prevention and treatment by providing the background for in vivo RNA nanotechnology.

Aging is a major risk factor for both cardiovascular and neurodegenerative diseases. The bidirectional communication between the heart and brain, commonly referred to as heart-brain crosstalk, is increasingly disrupted with age. In this review, we summarize current evidence linking cardiovascular and neurodegenerative disorders, particularly in the context of aging. We also discuss the underlying mechanisms responsible for the heart-brain crosstalk, including blood-brain barrier breakdown, vascular dysfunction, nervous system alterations, inflammation, and endocrine dysregulation, which may explain the frequent co-occurrence of dysfunction in both organs during aging. Understanding these interconnections provides critical insights into the pathophysiology of age-related diseases and highlights potential therapeutic targets to preserve both heart and brain health in the aging population.

Pericytes, which share markers with smooth muscle cells (SMCs), are heterogenous cells. Pericytes in the brain and skeletal muscle have different embryonic origins, representing distinct subpopulations. One challenge in the field is that there are no subpopulation-specific pericyte markers. Here, we compared the transcriptomes of muscle pericytes and SMCs, and identified 741 muscle pericyte-enriched genes and 564 muscle SMC-enriched genes. Gene ontology analysis uncovered distinct biological processes and molecular functions in muscle pericytes and SMCs. Interestingly, the Venn diagram revealed only one gene shared by brain and muscle pericytes, suggesting that they are indeed distinct subpopulations with different transcriptional profiles. We further validated that GSN co-localized with PDGFRβ⁺SMA⁻ cells in small and large blood vessels but not PDGFRβ⁺SMA⁺ cells, indicating that GSN predominantly marks pericytes and fibroblasts rather than SMCs in skeletal muscle. Negligible levels of GSN were detected in the brain. These findings indicate that GSN may serve as a selective marker for muscle pericytes.

Laminin exerts a variety of important functions via binding to its receptors, including integrins and dystroglycan. With the advance in gene-targeting technology, many integrin/dystroglycan knockout/mutant mice were generated in the past 3 decades. These mutants enable loss-of-function studies and have substantially enriched our knowledge of integrin/dystroglycan functions. In this review, we summarize the functions of laminin receptors during embryonic development and in the central nervous system and vasculature. First, the biochemical properties of integrins and dystroglycan are briefly introduced. Next, we discuss loss-of-function studies on laminin receptors, including integrin-α3, integrin-α6, integrin-α7, integrin-β1, integrin-β4, and dystroglycan, focusing on embryonic development, the central nervous system, and vasculature. The phenotypes of compound knockout mice are described and compared with that of single mutants. Last, important questions and challenges in the field as well as potential future directions are discussed. Our goal is to provide a synthetic review on loss-of-function studies of laminin receptors in the central nervous system and vasculature, which could serve as a reference for future research, encourage the formation of new hypotheses, and stimulate new research in this field.

The blood-brain barrier (BBB) is a dynamic structure that maintains brain homeostasis. BBB breakdown is a key pathological hallmark of almost all neurological diseases. Although the regulation of BBB integrity by different cells has been extensively studied, the function of its non-cellular component-the basal lamina in BBB regulation remains largely unknown. Laminin, a trimeric protein with multiple isoforms, is one of the most important constituents of the basal lamina. In the CNS, different cells synthesize distinct laminin isoforms, which differentially regulate BBB integrity in both physiological and pathological conditions. A thorough understanding of laminin expression and function in BBB integrity could lead to the identification of novel therapeutic targets and potentially result in effective treatments for neurological disorders involving BBB disruption. Here in this review, we first briefly introduce the BBB and basal lamina with a focus on laminin. Next, we elucidate laminin expression and its function in BBB maintenance/repair in a cell-specific manner. Potential functional compensation among laminin isoforms is also discussed. Last, current challenges in the field and future directions are summarized. Our goal is to provide a synthetic review to encourage novel ideas and stimulate new research in the field.

Intracerebral hemorrhage (ICH), the deadliest form of stroke, is characterized by bleeding into brain parenchyma and formation of hematoma. Currently, there is no treatment available for ICH. Inflammatory response is a key pathology of ICH and plays a dual role in ICH---contributing to both secondary brain injury and recovery processes. This review discusses different types (both brain-resident and infiltrated) of immune cells and their functions during inflammation processes following ICH. Specifically, the temporal dynamics, polarization, and function of microglia/macrophages, neutrophils, lymphocytes, and astrocytes in ICH are summarized in a cell-specific manner. In addition, we also discuss key challenges and unanswered questions that need to be addressed in the future. A thorough understanding of the functions of different immune cells in ICH will provide a strong foundation for future studies and lead to the identification of novel cellular/molecular targets for therapeutic development.

Background: Pericytes, a type of mural cells, exert important functions in the CNS. One major challenge in pericyte research is the lack of pericyte-specific and subpopulation-specific markers.

Methods: To address this knowledge gap, we first generated a novel transgenic mouse line in which vascular smooth muscle cells (vSMCs) are permanently labeled with tdTomato. Next, we isolated PDGFRβ⁺tdTomato^- pericytes and PDGFRβ⁺tdTomato⁺ vSMCs from the brains of these mice and subsequently performed RNAseq analysis to identify pericyte-enriched genes.

Results: Using this approach, we successfully identified 40 pericyte-enriched genes and 158 vSMC-enriched genes, which are involved in different biological processes and molecular functions. Using ISH/IHC analysis, we found that Pla1a and Cox4i2 were predominantly enriched in subpopulations of brain pericytes, although they also marked some non-vascular parenchymal cells.

Conclusions: These findings suggest that Pla1a and Cox4i2 preferably label subpopulations of pericytes in the brain compared to vSMCs, and thus, they may be useful in distinguishing these populations.

The article "MiR-411-5p acts as a tumor suppressor in non-small cell lung cancer through targeting PUM1" by L.-H. Xia, Q.-H. Yan, Q.-D. Sun, Y.-P. Gao published in Eur Rev Med Pharmacol Sci 2018; 22 (17): 5546-5553-DOI: 10.26355/eurrev_201809_15816-PMID: 30229827 has been retracted in accordance with the Publisher and the Editor in Chief. Following some concerns raised on PubPeer, the Journal has started an investigation to assess the validity of the results as well as possible figure manipulation. The journal's investigation confirmed several instances of Figure duplication with previously published articles, specifically in Figures 3 and 4. The authors were contacted, informed of the ongoing investigation, and requested to provide the original data supporting the manuscript, but they remained unresponsive. As a result, the Journal has decided to retract this article. This article has been retracted. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/15816.

The article "Boswellia serrata and Salvia miltiorrhiza extracts reduce DMN-induced hepatic fibrosis in mice by TGF-beta1 downregulation" by R. Sferra, A. Vetuschi, V. Catitti, S. Ammanniti, S. Pompili, D. Melideo, G. Frieri, E. Gaudio, G. Latella published in Eur Rev Med Pharmacol Sci 2012; 16 (11): 1484-1498-PMID: 23111960 has been retracted in accordance with the Publisher and the Editor in Chief. Following some concerns raised on PubPeer, the Journal has started an investigation to assess the validity of the results as well as possible figure and data manipulation. The authors were contacted and informed of the ongoing investigation. The authors stated that "due to an inadvertent error that occurred during the preparation of the manuscript, some images and data were mistakenly selected from an incorrect file, resulting in the inclusion of material previously published in Liver International (2009)". The article has been, therefore, retracted according to COPE guidelines. This article has been retracted. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/1806.