FET-CREB fusion-positive” has recently been identified in the literature and will be added to the 2021 World Health Organization Classification of Tumors of the Central Nervous System. However, our latest study using DNA-methylation analyses has revealed that intracranial FET-CREB fused tumors do not represent a single molecular tumor entity. Among them, the main subgroup presented classical features of angiomatoid fibrous histiocytoma, having ultrastructural features of arachnoidal cells, for. Another tumor type with clear cell component and histopathological signs of aggressivity clustered in close vicinity with clear cell sarcoma of soft tissue. Herein, we report one case of IMT with a novel SMARCA2-CREM fusion which has until now never been described in soft tissue or the central nervous system. We compare its clinical, histopathological, immunophenotypic, genetic and epigenetic features with those previously described in IMT, FET-CREB fusion-positive. Interestingly, the current case did not cluster with IMT, FET-CREB fusion-positive but rather presented histopathological , clinical , genetic (fusion implicating the CREM gene), and epigenetic (DNA-methylation profiling) similarities with our previously reported clear cell sarcoma-like tumor of the central nervous system. Our results added data suggesting that different clinical and histomolecular tumor subtypes or grades seem to be included within the terminology “IMT, FET-CREB fusion-positive”, and that further series of cases are needed to better characterize them.A novel histomolecular tumor of the central nervous system, the “intracranial mesenchymal tumor (IMT),  EWSR1 and FUS) with genes from the CREB (cAMP response element) family  are involved in a wide variety of tumors of various locations and prognoses . In the central nervous system (CNS), the recent literature identified a novel histomolecular type, named “intracranial mesenchymal tumor (IMT), FET-CREB fusion-positive” which will be added in the new WHO classification [FET-CREB fused do not represent a single molecular tumor type but different epigenetic subtypes according to DNA-methylation analyses [SMARCA2-CREM fusion. We compare its clinical, histopathological, immunophenotypic, genetic and epigenetic features with those previously described in IMT, FET-CREB fusion-positive.FET fusions . Moreover, initial and recent imaging of the whole body did not show other tumor locations. FISH analysis of the EWSR1 gene failed to reveal a rearrangement and RNA sequencing evidenced a SMARCA2-CREM gene fusion  and sarcomas (concomitant loss of SMARCA4 and SMARCA2 expressions) [SMARCA2-NR4A3 fusion (with the same breakpoint at SMARCA2 gene) [EWSR1) implicated in extraskeletal myxoid chondrosarcomas is replaced by the SMARCA2 gene, suggesting a similar molecular tumorigenesis. Previously, a wide spectrum of histopathology has been reported in FET-CREB fused tumors of the CNS, including chordoid morphology [FET-CREB fusion-positive but did not cluster with them when studied using DNA-methylation analysis. Moreover, it presents similar clear cell morphology, radiological features, histopathological signs of malignancy, pejorative outcome, CREM gene fusions, and epigenetic features to one reported CCS-like tumor of the CNS [IMT are characterized by recurrent ally FUS –9, 11–23essions) . Only onA2 gene) . As was A2 gene) . As the rphology , suggestFET-CREB fused genetic spectrum with one novel fusion that does not involve the EWSR1 gene. This current case constitutes the second CCS-like tumor having a worse prognosis than IMT, FET-CREB fusion-positive. Further studies are needed to characterize in detail this rare type of tumor and to validate the existence of different epigenetic tumor subtypes.In conclusion, we expanded the IMT,


Chimeric antigen receptor (CAR) therapy is based on patient blood-derived T cells and natural killer cells, which are engineered in vitro to recognize a target antigen in cancer cells. Most CAR-T recognize target antigens through immunoglobulin antigen-binding regions. Hence, CAR-T cells do not require the major histocompatibility complex presentation of a target peptide. CAR-T therapy has been tremendously successful in the treatment of leukemias. On the other hand, the clinical efficacy of CAR-T cells is rarely detected against solid tumors. CAR-T-cell therapy of cancer faces many hurdles, starting from the administration of engineered cells, wherein CAR-T cells must encounter the correct chemotactic signals to traffic to the tumor in sufficient numbers. Additional obstacles arise from the hostile environment that cancers provide to CAR-T cells. Intense efforts have gone into tackling these pitfalls. However, we argue that some CAR-engineering strategies may risk missing the bigger picture, i.e., that a successful CAR-T-cell therapy must efficiently intertwine with the complex and heterogeneous responses that the body has already mounted against the tumor. Recent findings lend support to this model. Chimeric antigen receptor (CAR) therapy is based on patients’ blood-derived T cells and natural killer (NK) cells, which are engineered in vitro to express artificial receptors to recognize a specific target antigen and the cells expressing that antigen  1]..1].The genetic modification of peripherally derived T cells with CAR was developed from the concept of adoptive immunotherapy using tumor-infiltrating lymphocytes (TIL) , whose TCAR-T cells were instead developed to recognize the target antigen through immunoglobulin antigen-binding regions. Hence, CAR-T do not require target-peptide presentation by MHC molecules. This correspondingly allowed CAR constructs to be used to direct the activity of NK cells .CAR-T cell therapy has been tremendously successful in the treatment of leukemias ,6,7,8, sCAR-T cell therapy for solid tumors faces many hurdles ,10, starIntense efforts have gone into tackling these pitfalls. However, we argue that some CAR-engineering strategies may risk missing the big picture, i.e., that a successful CAR-T-cell therapy must efficiently intertwine with the complex and heterogeneous responses that the body has already mounted against the tumor . Experimζ and a CD28 transmembrane domain, together with selective T-cell activating moieties, including the endodomains of CD28, OX40, 4-IBB, Lek, and ICOS  have shown enhanced activity, persistence, and efficacy -12 stimulate innate immune cells against the tumor and become resistant to Treg and MDSC . T cellsTRUCK approaches are being tested in early phase clinical trials. The NCT03182816 trial was started in 2017 as a phase I/II single-arm to determine the safety and efficacy of infusion of autologous T cells engineered to express immune checkpoint antibodies (CTLA-4 and PD-1) and chimeric antigen receptor targeting epidermal growth factor receptor (EGFR-CAR) in adult patients with EGFR-positive advanced malignant solid tumors. Eight of nine patients showed detectable EGFR-CAR-T cells in their peripheral blood. One patient had a partial response, which lasted >13 months, six had stable disease, and two had disease progression . The EGFAs mentioned above, the clinical efficacy of CAR-T cells observed in hematological malignancies is rarely found against solid tumors. Hematological malignancies are devoid of many of the physical immunosuppressive factors that hamper adoptively transferred cells from reaching solid tumors. Furthermore, target antigens that are present on hematological cancers are often homogenous and are expressed in most tumor cells. In contrast, target antigens on solid tumors are often heterogeneous both across tumors and between primary and metastatic sites. CAR-T cell therapy for solid tumors faces additional obstacles ,10, starEGFRvIII) [An appropriate choice of target antigens and the effective combination with immunostimulatory signaling have been shown to enhance CAR efficacy. CAR comprising the ICOS signaling domain liaises with the effective antitumor effect on gliomas that express the epidermal growth factor receptor variant III (EGFRvIII) . The preGFRvIII) , modifieGFRvIII) , cancer-GFRvIII) . CAR wasGFRvIII)  or tumorGFRvIII) . AdditioGFRvIII) .These combined efforts have led to a burgeoning of clinical trials in the field, the majority remaining focused, though, on leukemias and lymphomas . FDA-appThe persistence, trafficking, and maintenance of function remain a challenge in many CAR-T approaches. Using intravital imaging, anti-CD19 CAR-T cells were tracked at lymphoma sites . HoweverThe anticancer activity of CAR-T can associate with life-threatening toxicity due to the increased secretion of pro-inflammatory cytokines  and the immune effector cell-associated neurotoxicity syndrome (ICANS) as mediated by the simultaneous activation of large numbers of T cells ,58. ThisCytokine release is usually greater with CAR containing CD28 versus 4-1BB co-stimulatory domains. On the other hand, constructs with either domain confer similar anticancer activity in mouse models. T cell products expressing CAR with either CD28 or 4-1BB co-stimulatory domains have been highly efficacious in patients with relapsed hematological malignancies, and anti-CD19 CAR showed similar activity regardless of the source of the co-stimulatory domain. In large-cohort clinical trials, the rates of neurological toxicities have been higher with CD28–co-stimulated CAR, although this finding is probably the result of multiple converging factors rather than due to CD28 signaling alone . One of Intense cytokine release is associated with T-cell activation upon engagement with target cells, which leads to higher levels of circulating cytokines, including IL-6 and interferon γ. Consistently, elevated levels of serum cytokines are less common in patients who do not have a clinical response after CAR-T cell therapy .NK cells produce several cytokines, including tumor necrosis factor α, interferon γ, and IL-10 . NK cellA major concern of CAR-T therapy is that CAR-T cells may become exhausted or dysfunctional ,67, whicCAR-T cell exhaustion is considered the outcome of the chronic tumor stimulation imposed on T cells, which leads to disruption of their function . Proof oCell exhaustion may differentially affect T cell subpopulations, suggesting a relationship with the selection procedures utilized to manufacture CAR-T cells. Optimal cell subpopulations for adoptive cell transfer were suggested to be those that retain their memory/naïve capacities  to permiEpigenetic profiles regulate the gene expression of key transcription factors over immune cell differentiation and proliferation pathways. Through a screening of chemical probes with defined epigenetic targets, JQ1, an inhibitor of bromodomain and extra-terminal motif (BET) proteins, was found to maintain CD8+ T cells with functional properties of stem cell–like and central memory T cells . AdoptivThe altered differentiation of CAR-T cells can also accompany T cell exhaustion . UtiliziA major hurdle to be overcome by tumor-infiltrating CAR-T cells is immunosuppression. T cell exhaustion itself was shown to be an outcome of cancer-associated immunosuppression. Correspondingly, resistance to exhaustion was shown to be linked to interaction with other cancer-infiltrating cell types .Cancers contain a broad ensemble of genetically normal cells within an extracellular matrix (ECM), which was collectively termed the tumor microenvironment (TME), that substantially diverges from normal stroma. This has fostered the concept that tumors grow as integrated tissues or organs, that combine diverse components, such as vasculature, nerves, an immune environment, and connective tissue.βRII) expression in CAR-T cells [ClinicalTrials.gov: NCT03089203) [TGF-β is a key driver of immunosuppression ,38,39. P-T cells . This le3089203) . Knockin3089203) . Additio3089203) .Metabolic conditions can negatively impact on CAR-T cell function: among them, an increase in the acidity of the TME because of increased glycolysis by cancer cells. This ‘Warburg effect’ ,77 stemsOne of the approaches used to fight immunosuppression has been the generation of CAR-T cells expressing cell-surface dominant-negative receptors (DNR) to override the inactivating signals present in the TME. DNR can be generated with a functional extra-cellular domain and a mutation in the intracellular region to abolish downstream signal transduction. DNR can effectively compete with their endogenous counterparts. The use of DNR for immunosuppressive factors such as TGF-β has endowed transduced EBV cells with resistance to immunosuppression . A DNR fγ and cytotoxicity and were more resistant to immunosuppression in TME.The reduction of inhibitory signaling pathways in T cells has shown promise in T-cell reactivation. The inhibition of Protein Kinase A with Ezrin using a ‘regulatory subunit 1 anchoring disruptor’ (RIAD-CAR) resulted in an upregulation of CXCR3 and CD49D integrin (VLA-4), which resulted in enhanced RIAD-CAR-T cells trafficking to tumors and better migration to CXCL10 in vitro . RIAD-CAIL-8 release within tumors was utilized to enhance intratumoral T-cell trafficking. Modified CAR inducing the expression of IL-8 receptors, CXCR1 or CXCR2, showed enhanced migration and persistence of T cells in the tumor. This induced complete tumor regression and long-lasting immunologic memory in preclinical models of glioblastoma, ovarian, and pancreatic cancer .TGF-β-resistant EGFRvIII CAR-T cells were shown to possess higher antitumor efficacy in murine glioma models , and proThe approaches described above supported the feasibility of ‘multi-targeted CAR-T’. The rationale was to improve selectivity for cancer cells and to reduce the off-tumor effects based on the presence or absence of two target antigens. This was also expected to lead to enhanced cytotoxicity and to reduce chances of antigen escape variants. Early work showed the synergistic effects of two individual CAR against two separate targets, i.e., folate binding protein and Her-2, together with limited antitumor efficacy in the presence of only one . Dual CADistinct intracellular signaling domains were also engineered onto different CAR recognizing two separate target antigens , both prDual recognition was also exploited to direct CAR-T cells to the tumor target (CAR one) and then kill cancer cells (CAR two). One of these approaches utilized a Synthetic Notch receptor (SynNotch) with an extracellular CAR specific for a target antigen, which was fused to an intracellular cleavable transcriptional domain. Binding to the target antigen resulted in Notch cleavage and the downstream transcriptional activation of Notch-inducible genes . Then, aDual CAR design can also be exploited to enhance signaling by 4-1BB and CD28 domains, which is best achieved by the membrane proximal positioning of both signaling units, within separate, parallel CAR .Artificial intelligence scrutiny of bulk, single-cell, and spatially resolved gene expression data of CAR-T targets  have proT cells mediate antitumor immune responses and are the key target of immune checkpoint therapy, but they can also promote immune tolerance. A clear understanding of the specific contributions and biology of different T cells subsets is required to fully harness the curative potential of immunotherapies . Treg arMDSC constitute a subset of immune cells that can have immunosuppressive activity in the TME ,69. Throγ and enhancement of antitumor T-cell responses [The modulation of MDSC function in cancers has achieved remarkable progress. Neutralizing antibody to KIT significantly reduced MDSC expansion and relieved T cell immunosuppression in colon cancer . Antagonesponses .Tumor-associated macrophages (TAM) play a key role in the regulation of tumor immunity ,69. The A subset of TAM expresses folate receptor β (FRβ) and possesses an immunosuppressive M2-like profile. Anti-FRβ CAR-T cells targeting TAM achieved the selective elimination of FRβ+ TAM in the TME, resulting in an enrichment of pro-inflammatory monocytes, influx of endogenous tumor-specific CD8+ T cells, delayed tumor progression, and prolonged survival in murine models of ovarian cancer, colon cancer, and melanoma .Advanced approaches of TAM depletion rely on the inhibition of colony-stimulating factor 1 and its receptor (CSF1/CSF1R) signaling ,115. VarBisphosphonates significantly reduced TAM infiltration in lung cancer, melanoma, hepatocellular carcinoma, and lung metastasis from breast cancer . A direcThe blockade of monocyte recruitment to tumors was utilized as an alternative approach to reduce TAM infiltration. Inhibitors of the chemokine CCL2 or of CCR2, i.e., the receptor for CCL2, have been utilized to this end. CCR2 antagonists inhibit monocyte recruitment and TAM M2 polarization in hepatocellular carcinoma . PF-0413IL-10 is a TAM-derived cytokine with the ability to block IL-12 and suppress T-cell tumoricidal function . InhibitToll-like receptors (TLR) play a critical role in innate immune response and polarize macrophages into a pro-inflammatory subtype. Agonists of TLR7, TLR8, and TLR9 were shown to revert macrophage polarization and increase tumoricidal activity in several cancer models .Broader approaches to TAM reprogramming include inhibition of DICER, a pivotal enzyme for microRNA synthesis , and inhNevertheless, caution must be exerted, as TAM reprogramming is hampered by acquired resistance and compensation by alternative immunosuppressive circuits, and it bears serious side effects, including anemia and autoimmunity .Recent studies have demonstrated a role for B cells in antitumor immunity. The presence of B cells in tumor was associated with a better response to neoadjuvant therapy with ICB in melanoma and renal cell carcinoma. B cells were found primarily in tertiary lymphoid structures (TLS). Tumor-infiltrating B cell populations in responder tumors were enriched in memory B cells. In contrast, naive B cells were more prominent in non-responder tumors. Similarly, in soft-tissue sarcomas, the presence of TLS enriched in B cells was associated with a better response to PD-1 blockade. The mechanism underlying the effect of B cells on response to adoptive immunotherapy is poorly understood. However, mechanisms include the activation of T cells through antigen presentation by memory B cells and B cells-derived cytokines, as well as potential contribution through the production of anticancer antibodies. Future studies are required to determine the precise mechanism of action for these cells as well as the different components of TLS ,130,131.Other innate immune cells infiltrating the tumor microenvironment, such as NK cells, neutrophils, and DC, can further impact antitumor immune responses. NK cells are cytotoxic lymphocytes that identify target cells in the absence of MHC. NK cells can elicit rapid immune responses , and theWithin the TME, cancer-associated fibroblasts (CAF) assume the role of organizers and direct the recruitment and differentiation of TME-infiltrating cells . These CECM-producing CAF  are characterized by the expression of PDPN (podoplanin), FAP, ACTA2 (actin α2), COL1A1 (collagent type I α1 chain), and COL1A2. CAF, in addition to ECM-crosslinking enzymes and ECM components, produce ECM-degrading proteases, such as matrix metalloproteinases, for ECM remodeling ,139. VasCAF can exert broadly divergent functions on tumor cells . CAF witvCAF can induce tumor progression via the secretion of CXCL12 and VEGF, which promote angiogenesis. However, CXCL12 and CXCL5 inhibit T cell migration into the tumor . T cellsCAF can actively influence cancer cells and immune cells through the production of various metabolites, including alanine , aspartaCAF with tumor-restraining functions promote antitumor immunity, generate a pro-inflammatory secretome, provide tumor-inhibitory signaling, and produce ECM components, which enhance intra- and peri-tumoral fibrosis, and correspondingly reduce tumor cell invasion and dissemination capacity. Higher tumoral αSMA levels and stromal densities are associated with higher overall survival in patients with pancreatic cancer ,153. TarAs suggested above, increasing experimental evidence indicates that a successful CAR-T-cell therapy must efficiently intertwine with the complex and heterogeneous responses that the body has already mounted against the tumor . A robusCellular and humoral responses are highly dynamic in response to infection and cancer . ConsistAs tumors evolve, the tumor microenvironment gradually becomes more immunosuppressive with several components of the innate and adaptive immune system contributing to tumor immune evasion and to resistance to immunotherapeutic tools. A key player in immunosuppression is TGF-β, and TGF-β-counteracting therapies have shown favorable impact in distinct settings . HoweverThe interaction of CAR-T cells with immunoregulatory environments has been shown by CAR-T memory formation and function via hematopoietic stem cells (HSC) , which wCAF induce the differentiation of tumor-associated mast cells (MC), which are known to induce angiogenesis and modulate chronic inflammation  and poteThe analysis of spatially-defined immune landscapes of triple-negative breast cancer (TNBC) showed distinct clinicopathologic features, RNA-based immune signatures, and spatially defined protein-based tumor–immune microenvironment in early-stage PD-L1+ and PD-L1−TNBC. PD-L1+ stromal and intraepithelial cells showed spatially specific alterations in CTLA-4, and spatially defined PD-L1+ cells were enriched in several clinically actionable immune proteins, with an impact on therapy efficacy and disease outcome. Gene expression signatures obtained from single-cell RNA sequencing have correspondingly been used to characterize CAR-T strategy outcomes, CAR design impact, and combination with ancillary therapies .Mentions of functional interaction of CAR-T cells with endogenous immune cell subpopulations are reported in the relevant subject sections above. However, a special mention is required here for experimental approaches that were explicitly designed to impact on such cell subpopulations.In addition to their direct cytotoxic effect, allogeneic CAR invariant NKT (CAR-iNKT) cells were found to exert potent antitumor effects through the cross-priming of CD8-T cells . This reCAR-T engineered to secrete the combination of CCL19, and IL-7 were found to recruit endogenous immune cells and favor the generation of memory cells against cancer cells . In a syThe surface expression of 4-1BBL on CAR-T cells was proposed to remodel the TME through the autocrine-induced secretion of type I IFN, which improves DC cross-priming, Treg inhibition, and angiogenesis suppression .CD40L expression on CD19 CAR-T cells resulted in the elevated surface expression of co-stimulatory molecules, adhesion molecules, HLA molecules, and the Fas death receptor on CD40+ tumor cells, thus increasing their immunogenicity . These TT cells engineered to secrete Fms-like tyrosine kinase 3 ligand (Flt3L), a hematopoietic cell growth factor, promote intratumoral DC1 and DC-precursor proliferation . FurtherFinally, CAR-T cells can be engineered to facilitate the engagement of tumor cells by endogenous, non-engineered T cells through the secretion of bispecific T-cell engagers (BiTE), which are composed of two fused scFvs . An examFuture research directions may benefit from designing anticancer CAR-T strategies according to the complexity of immune cells and stromal populations in the cancer milieu. The potential crosstalk among different engineered features within the CAR-T cells, as well as with endogenous immune cells, tumor cells, and TME, requires being taken into consideration for enhancing CAR-T cell therapy and reducing toxicity in the treatment of solid tumors.To enhance synergy with endogenous T cell signaling appears to be an effective strategy for improving anticancer responses . Treg caThe role of B cells in anticancer responses has only recently been explored. B cells largely reside in lymphoid aggregates. These were enriched in memory B cells in responder tumors, suggesting the course of an effective antitumor response. The mechanism underlying the effect of B cells in response to adoptive immunotherapy is poorly understood. B cells may activate T cells through antigen presentation by memory B cells and B cells-derived cytokines ,130,131.Inhibiting the activity of M2-like TAM and redirecting the polarization of macrophages toward the M1 phenotype appears to be a promising approach to enhance response to adoptive immunotherapy . As typeNK cells, neutrophils, and DC infiltrate the tumor microenvironment and further impact antitumor immune responses. The activation of NK cells leads to the recruitment and activation of other effectors cell subsets, such as dendritic cells, macrophages, and neutrophils, and to the subsequent activation of antigen-specific T and B cell responses. Tumor-infiltrated neutrophils have shown both pro- and antitumor phenotypes.Corresponding conditioning regimens/ablation of immunosuppressive cell subpopulations and CAF subtypes before CAR-T cell infusion may pave the way for higher efficacy. The discovery of the tumor-restraining functions of CAF may provide a potential explanation for the unsuccessful clinical trials of therapeutic agents targeting CAF or stromal components. These observations suggest that future therapeutic strategies should avoid the generic targeting of tumor-restraining CAF subpopulations, rather favoring targeting tumor-promoting CAF subsets. FAP-expressing CAF can have an immunosuppressive function, which might present an opportunity for improving immunotherapies via the depletion of these CAF or targeting CAF-derived factors such as CXCL12 or CCL2.Finally, state of the art approaches, such as single-cell sequencing, as well as proteomic and metabolomic analyses, are helping to dissect the heterogeneity and functional interactions of different cell types in the tumor microenvironment. This acquired knowledge may significantly enhance our ability to manage these complex interactions for the engineering of the next generations of CAR for solid tumor therapy ,93,173.


Novel Theranostic Agents, nine original articles from around the globe provide further evidence on the use of the theranostic concept for neuroendocrine neoplasm (NEN), prostate cancer (PC), meningioma, and neuroblastoma. The investigated diagnostic and therapeutic radiotracers target not only established structures, such as somatostatin receptor, prostate-specific membrane antigen or norepinephrine transporter, but also recently emerging targets such as the C-X-C motif chemokine receptor 4. Moreover, the presented original articles also combine the concept of theranostics with in-depth read-out techniques such as radiomics or novel reconstruction algorithms on pretherapeutic scans, e.g., for outcome prediction. Even 80 years after its initial clinical introduction, theranostics in oncology continues to thrive, now more than ever. Tracing its roots back to the 1940s, theranostics in nuclear oncology has proved successful mainly due to the beneficial effects of image-guided therapeutic concepts for patients afflicted with a variety of different cancers. The majority of these treatments are not only characterized by substantial prolongation of progression-free and overall survival, but are also generally safe, rendering theranostic agents as an attractive treatment option in various clinical scenarios in oncology. In this Special Issue  Tracing its roots back to the 1940s . Recent 131I]meta-iodobenzylguadinine ([131I]mIBG) scans in children afflicted with neuroblastoma, elegantly demonstrating that post-therapy imaging can provide further information on the extent of disease relative to pretherapeutic SPECT performed for diagnostic purposes. As such, [131I]MIBG scans acquired after therapy should be closely examined so that relevant sites of disease will not be missed DTPA-octreotide scintigraphy in GEP-NEN patients treated with everolimus. They identified the radiomics parameter of lesional asphericity (ASP) as an independent predictor for outcome, thereby suggesting that ASP may serve as a risk stratification tool prior to treatment onset Pentixafor, which can also be used in a theranostic setting using its 177Lu-labeled twin Pentixather, in hematological malignancies [68Ga]Pentixafor [18F]fluoro-D-glucose ([18F]FDG) in this clinical scenario. Nonetheless, uptake was still substantial on CXCR4-directed imaging and the lesion-based heterogeneity of [18F]FDG-avid and [68Ga]Pentixafor-negative lesions, and vice versa, should be further explored for outcome prediction [DOTA0-Phe1-Tyr3] octreotide ([68Ga]DOTATOC) PET is highly useful in this scenario DCFPyL and reported on the use of point-spread function (PSF) for a more appropriate categorization of indeterminate PSMA-RADS-3A to (more definitive) PSMA-RADS-4 lesions, which renders PSF reconstructions for PSMA-targeted PET as a useful tool to increase interpretative certainty PSMA-617 for radioligand therapy for PC. First, Völter et al. analyzed PC patients who had undergone PSMA-targeted therapy [177Lu]PSMA-617 and Völter and colleagues demonstrated that this approach provided a fast and feasible dosimetry read-out for response assessment. Therefore, relative to time-consuming dosimetry of the entire tumor burden, such a simplified procedure of analyzing post-therapeutic SPECT may be more practical for clinical routine [68Ga]PSMA PETs and reported on the usefulness of such mathematically extracted scan signatures for outcome prediction in patients scheduled for [177Lu]PSMA [The last two original articles refer to the use of [ therapy . For PSM therapy . Therefo routine . Post-th7Lu]PSMA .We hope that the readers of this Special Issue enjoy the broad content as much as we did. Taken together, even 80 years after the initial introduction of using radioiodine for thyroid cancer, theranostics in oncology is definitively alive and increasingly relevant.


Multiple myeloma (MM) is an indolent B-cell malignancy, where treatment is aimed at preventing organ dysfunction from light chain accumulation (slowing disease progression) and inducing remission. Allogeneic stem cell transplant , through graft versus myeloma (GVM) effects, has the potential to induce remission to a potentially curative-like state. In this systematic review, we aimed to understand this relationship to the risks and severity of disease in categorized patients and gain an updated comprehension of the future of allo-SCT in MM treatment. We conducted this review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and searched the PubMed database to obtain the specified literature with both the use of keywords and Medical Subject Headings (MeSH). A total of 16 relevant articles were included for discussion after the quality appraisal was completed, as appropriate, by either the Cochrane tool or Newcastle-Ottawa checklist. Our review concludes that while allo-SCT may benefit high-risk patients, successful procedures may incorporate a tandem autologous hematopoietic stem cell transplant approach in combination with novel pharmacologic contributions for which there is an observed synergy in the modulation of the immunologic microenvironment. Furthermore, tailored patient selection by evaluating pre-transplant factors including high-risk cytogenetics, age, and pre-salvage International Staging System (ISS) can predict post-transplantation success including non-relapse mortality. Successive research should continue to revise and update treatment options as the evolving therapeutic drug regimens may change over the course of indolent disease. Multiple myeloma (MM) affects five in every 100,000 people yearly . It is aCurrently, the treatment of MM is aimed at preventing organ dysfunction from light chain accumulation (slowing disease progression) and inducing remission in far-progressed patients ,7. AlthoAllogeneic hematopoietic stem cell transplantation  has the potential to induce remission to a potentially curative-like state through graft versus myeloma (GVM) effects . SustainBoth allo-SCT and auto-SCT, despite procedural advances, may incur significant morbidity and mortality even with tailored patient selection ,18. DuraCurrently, allo-SCT is considered a viable treatment option only in patients with severe disease . While tMethodsProtocolWe performed a systematic review following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .Inclusion/Exclusion CriteriaWe conducted a literature search to identify studies that assessed MM and stem cell transplantation (SCT), particularly allo-SCT. The criteria implored to gather relevant articles included (1) MM patients treated with allo-SCT and (2) any outcomes in MM patients considered for allo-SCT. We focused on chronic multiple myeloma patients without any age or gender discrimination. Articles that reported on MM patients undergoing auto-SCT without consideration for allo-SCT or MM exclusively treated with non-transplant therapy were ultimately out of the scope of this study and therefore were excluded.Search StrategyWe systematically searched articles indexed in PubMed  and Scie Table Data ExtractionOnce the relevant articles were collected by authors AK and JP, the titles and abstracts, and full-texts were utilized in the final decision to include studies for discussion. Two independent researchers, AK and JP, convened on the decisions for scrutiny and accuracy.Risk of Bias AssessmentThe studies were assessed, as appropriate, to include those with moderate-to-high quality, with the following tools: (1) Newcastle-Ottawa checklist or (2) Cochrane risk-of-bias tool.ResultsSearch OutcomeWe collected relevant articles from PubMed, PubMed Central (PMC), Medline, and ScienceDirect databases. No other articles were identified using other sources. Our initial search yielded 164,795 articles without any restrictions. Once the inclusion/exclusion criteria were applied, 5,269 articles were attained: 3,904 identified with keywords and 1,365 using the MeSH strategy. After duplicates were removed , 3,957 articles were screened by title and abstract for relevance, following which 3,773 non-relevant articles were excluded. Abstracts and full text of the 184 relevant articles that remained were thoroughly read, and 151 of them were excluded based on eligibility. A final quality assessment yielded 16 moderate-to-high quality observational and randomized control trials for inclusion in the review while the remaining 17 were further excluded. Figure A total of 16 peer-reviewed studies from 2016 to 2021 with free full texts that discussed the treatment of MM with allo-SCT were chosen for inclusion. They included both observational studies (n = 15) and randomized control trials (n = 1) with moderate-to-high quality based on the conducted bias assessment. The findings of these studies are summarized in Table DiscussionOur systematic review assessed 16 previously published studies to formulate a better understanding of the potentially curative results of allo-SCT in MM patients and its relationship to the risks and severity of disease in categorized patients. We intend to gain an updated comprehension of this relationship and the future of SCT in MM treatment. Combinative-Comparative Features in Allogeneic and Autologous SCTBoth allogeneic and autologous SCTs offer beneficial treatment options for eligible MM patients. The first-line treatment for newly diagnosed, transplant-eligible patients is high-dose pharmacotherapy with auto-hematopoietic cell transplant (HCT); however, conditions for treatment are stringent and concerns in previous studies involving auto-HCT involve high-risk cytogenetics (poor risk MM), including post-treatment time to relapse ,31. A smNevertheless, a continued revision of therapy creates potential treatment options for patients in various categories. A study by Gagelmann et al. evaluated both clinical and cytogenetic data to assess patients with extramedullary disease undergoing auto-allo transplant, tandem autologous, or single-autologous transplant . They foA study by Giaccone et al. assessed drug-based treatment with combined autologous stem cell transplant and either (1) nonmyeloablative allo-SCT or (2) double auto-SCT . MoleculPharmacologic Contributions to SCTThe role of pharmacotherapy is exigent in allowing transplant intervention to take place. Nevertheless, new drug therapies are constantly evolving the landscape of treatment: the study by Van Elssen et al. describes haplo-BMT in MM may be a possible platform for future immunotherapeutic strategies utilizing the KIR-ligand mismatch; however, not necessarily with post-transplantation cyclophosphamide . ImmunopAllo-HCT can modify the immuno-microclimate, which can contribute to the therapeutic response of drug regimens; however, many patients ultimately relapse after allo-HCT: the study by Lopez-Corral et al. investigated the safety and efficacy of relapsing MM patients post-allo-HCT . They foA phase IIa clinical trial by Chen et al. tested the concept that increasing regulatory T cells (Treg) may mitigate the risk of GVHD post-allo-HCT using RGI-2001, a synthetic derivative of a CD1 ligand that perpetuates invariant natural killer cells . AlthougHowever, not all theorized therapeutics are clinically effective, as evaluated by Carlsten et al. in the premature termination of a study on SMM involving IPH2101 hypothesized to induce KIR-ligand mismatched tumor killing through natural killer cells and could be shown in vitro but was limited in vivo by antibody-induced hypo-responsiveness . They coPeri-Transplant Factors Affecting Patient OutcomeWhile MM is considered largely incurable, patients who develop resistance to therapeutics may have hope for a curable-like state with allo-HCT . HoweverGenetically defined high-risk MM in a subset of young patients with 17p deletions may experience limited remissions despite consistent therapeutic intervention . SeveralLimitationsAllo-SCT seems to have a promising future in the continued treatment of MM; however, some limitations are foreseeable due to the chronic nature of the disease and long-term follow-up necessary to provide insight into treatment efficacy. In this study, there are limitations in that we focused on PubMed and ScienceDirect indexed articles published in the English language, and studies before 2016 were not included. Our review focused on original research in the form of either observational studies or RCT; however, further insight into a conglomeration of research could be gained by assessing other review articles as well.In this systematic review, we aimed to evaluate the current literature on the use of allo-SCT in MM patients and under what circumstances this approach is feasible, preferred, and cautionary. Our review assessed studies that discussed the treatment of MM patients with allo-SCT or any outcomes in MM patients related to allo-SCT. We discussed that while allo-SCT may benefit high-risk patients, successful procedures may incorporate a tandem auto-SCT approach. Moreover, pharmacologic contributions are especially appreciated in allo-SCT due to an observed synergy in the modulation of the immunologic microenvironment. Tailored patient selection is a necessary consideration in projected clinical decisions. By evaluating pre-transplant factors including high-risk cytogenetics, age, and pre-salvage ISS, an estimated success rate can improve expected outcomes in allo-SCT-treated MM patients. The future of allo-SCT in MM treatment may benefit from large-scale studies. Given the chronic nature of MM and long-term follow-up necessary to achieve long-term survival data, subsequent reports should keep in mind the advancements in drug therapy and continue to revise and update the data pertaining to achievable results. Specific recommendations based on peri-transplant factors should also be further clarified in successive research.


This article reviews the descriptive data on the administration dose, administration method, mucosal injury site, and morphological characteristics of inflammatory sites of various NSAIDs. The cells, cytokines, receptors and ligands, pathways, enzyme inhibition, bacteria, enterohepatic circulation, oxidative stress, and other potential pathogenic factors involved in NSAID-associated enteropathy are also reviewed. We point out the limitations of drug modeling at this stage and are also pleased to discover the application prospects of chemically modified NSAIDs, dietary therapy, and many natural products against intestinal mucosal injury.With the wide application of non-steroidal anti-inflammatory drugs (NSAIDs), their gastrointestinal side effects are an urgent health burden. There are currently sound preventive measures for upper gastrointestinal injury, however, there is a lack of effective defense against lower gastrointestinal damage. According to a large number of previous animal experiments, a variety of NSAIDs have been demonstrated to induce small intestinal mucosal injury  Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs worldwide . Their mA convenient way to study the pathogenesis and complexity of NSAID-associated enteropathy in humans is to establish animal models. Although disease models established using animals cannot wholly represent human disease, we can study the typical pathological features they present with. Animal models of NSAID-associated enteropathy are essential for better understanding the histopathology of the small intestine and the causative factors at different stages. In addition, animal models play a significant role in exploring effective therapeutic and preventive measures and analyzing therapeutic modalities’ possible mechanisms of action. Researchers have successfully used a wide variety of NSAIDs to establish disease models in rodents, including indomethacin , diclofeIn this section, we mention a variety of NSAIDs that can cause damage to the small intestinal mucosa. We review the dosing regimens and measured variables in these papers in As early as 1969, researchers accidentally discovered intestinal damage while studying the anti-inflammatory effect of indomethacin . SD ratsIn 1990, some researchers explored gastrointestinal ulcers caused by anti-inflammatory drugs. They found that oral administration of diclofenac (15 or 30 mg/kg body weight) or intravenous injection of diclofenac (30 mg/kg body weight) could cause significant damage in the small intestine. However, the ulcerogenic effect of diclofenac was not as strong as that of indomethacin . Now, diAspirin is the most widely prescribed nonsteroidal anti-inflammatory drug (NSAID) worldwide. As early as 1970, D A Brodie and his colleagues used a blue dye so that small intestinal damage in rats that were orally administered aspirin could be observed grossly. At that time, aspirin-related enteropathy had not received much attention . With thFlurbiprofen increased intestinal permeability in rats after intraperitoneal or oral administration, confirming the systemic and local effects of the drug. Interestingly, investigators have found that this drug has an “adaptive” effect, that is, with continuous application of the same dose, there is a gradual decrease in intestinal permeability . Its ulcerogenic potency was significantly reduced after flurbiprofen was modified into an amino-alcohol ester derivative. Chemical modification of drugs effectively reduces their gastrointestinal toxicity .Oral administration of naproxen (80 mg/kg) to rats for 2 days resulted in medial intestinal injury, shortening of villi, and deepening of crypts . NaproxeSubcutaneous injection of indomethacin (100 or 300 mg/kg) could produce small intestinal injuries in unfasted mice. However, approximately ten times the dose of loxoprofen was required to produce the same ulcerogenic effect as indomethacin with loxoprofen . MultiplOral administration of 100 mg/kg ibuprofen to SD rats produced grossly visible small intestinal mucosal damage . A combiin vivo models  derived from Wistar rats to assess NSAID toxicity. Typical tissue damage could be observed in diflunisal-induced precision-cut intestinal slices, indicating the high intestinal toxicity of diflunisal . Howevero models . After aIt has been documented that 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) thiophene  was used to induce ileal ulcers in rats successfully . The cliParacetamol leads to intestinal damage by inducing a process of apoptotic cell death of LGR5+ stem cells in the intestinal crypts, and the intestinal barrier function of paracetamol-treated mice is affected for a long time . ParacetAlthough ketoprofen and indomethacin are both carboxylic acid-containing NSAIDs, ketoprofen is significantly milder in causing small intestinal mucosal injury . AdminisThis section focuses on displaying the pathogenetic factors involved in the above NSAID-associated enteropathy one by one.Cyclooxygenase (COX) is a crucial enzyme catalyzing the formation of prostaglandins. At present, it has been found that COX has two isoenzymes. COX-1 is a constitutive type, mainly present in blood vessels, stomach, kidney, and other tissues, involved in the regulation of vascular relaxation, platelet aggregation, gastric mucosal blood flow, gastric mucus secretion, and renal function. COX-2 is an inducible type. Various chemical, physical, and biological factors activate phospholipase A2 to hydrolyze cell membrane phospholipids to generate arachidonic acid, which COX-2 catalyzes to generate prostaglandins .COX inhibition alone was insufficient to induce small intestinal injury in rats . The patATP channels, which prevented phosphorylation uncoupling  is a bile acid sensor. FXR gene ablated mice were more prone to develop severe intestinal injury in response to naproxen. FXR activation by GW4064 protected against small intestinal damage caused by naproxen . The comKey enzymes of the NSAID metabolic pathway, such as cytochrome P450 enzymes and UDP-glucuronosyltransferase, are regulated by the nuclear receptor progesterone X receptor (PXR). It has been reported that the use of PXR agonists does not aggravate the ibuprofen-induced intestinal injury, demonstrating that PXR signaling is not a causative factor in ibuprofen-induced enteropathy . PXR-defThe activation of bile acid receptor TGR5 on intestinal L cells indirectly up-regulates the expression of glucagon-like peptide GLP-2 and increases intestinal HCO3- secretion by amplifying the amino acid-taste receptor 1 family heterodimer T1Rs—calcium pathway, revealing its intestinal mucosal protective effect and predicting its intestinal ulcer treatment prospects . It has In LPS activated RAW264.7 macrophages, the interaction of the ligand calcitroic acid/vitamin D with the vitamin D receptor (VDR) significantly reduced the expression of iNOS and IL-1β, reflecting the anti-inflammatory properties mediated by the VDR . A recenDeoxycholic acid (DCA) enhanced ileal lymphocyte migration in part by up-regulating adhesion molecule expression through sphingosine-1-phosphate receptor 2 (S1PR2), and S1PR2 antagonist alleviated indomethacin-induced and DCA-exaggerated small bowel injury . Bile acThe NSAID-induced small intestinal injury was associated with bacterial overgrowth . NSAID-iE. coli has been reported to aggravate NSAID enteropathy. After the heated E. coli strain administration, the number of ileal ulcers was significantly increased (Eubacterium limosum strain ATCC8480 or Escherichia coli strain W3110) had a higher ulcer formation rate than germ-free rats after BFMeT administration. However, it did not induce ulcers in any gnotobiotic rats treated with antibiotics  inhibited oxidative stress and inflammatory factor expression, corrected defective antimicrobial activity, enhanced the intestinal epithelial barrier, ensuring intestinal health in patients treated with NSAIDs . Intestinal inflammation triggered by activation of the LPS/Toll-like receptor signaling pathway is a crucial mechanism . Rats trThe innate immune sensors PRRs-toll-like receptors (TLRs) can trigger the innate immune system through various stimuli, such as exogenous microorganisms or endogenous danger signals . Activatvia a TLR4/MyD88-dependent pathway  mice to reveal an essential role for IL-17A in the development of indomethacin-induced small intestinal injury. IL-17A played a proinflammatory role through the up-regulation of G-CSF, KC, and MCP-1, all of which are chemokines. IL-17A may be a new target for treating NSAID-associated enteropathy . As thisvia the administration of hemin  could be induced by cytokines and bacterial lipopolysaccharide to produce sustained and large amounts of NO. NO in tLysozyme, an antimicrobial protein produced by Paneth cells, is involved in the innate immune response. It promotes the lysis of bacteria, and it effectively protects against inflammation at mucosal sites . ResearcIn addition, appropriate innate immune responses to microbes require complex interactions of several receptors, such as TLRs, protease-activated receptors (PARs) . We haveNSAID-associated enteritis is associated with feeding conditions. No lesions were found in the small intestine of fasted rats. The intestinal injury was observed in some rats fed continuously, and intestinal lesions were detected in most rats refed after starvation in the predrug period . Food anFood intake has been demonstrated to be important for the development of intestinal lesions. Sustained reduction of small intestinal lamina propria lymphocytes after a high-fat diet feeding exacerbated indomethacin-induced small intestinal injury . InsolubNSAID-induced autophagy inhibition impaired the integrity of the mucus layer combined with the inability of intestinal epithelial cells to clear intracellular pathogens, which elicited an uncontrolled inflammatory response eventually . Pure toGenetic susceptibility is strongly associated with intestinal inflammation. In genetically susceptible Lewis rats, the plasma kallikrein-kinin system was activated, associated with both acute and chronic phases of intestinal injury .It has been reported that psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans, which is inhibited by mast cell stabilizers, revealing a close association between the central nervous system and gastrointestinal function in humans .In a water avoidance stress model, psychological stress caused changes in intestinal microbiota, increased intestinal permeability, and deterioration of NSAID-associated enteropathy, all of which were ameliorated by the GR antagonist, mifepristone .via the 5-HT3 receptor. On the other hand, it exerted an anti-ulcer effect via the 5-HT4 receptor  and peroxisome proliferator-activated receptor α(PPARα), may play an essential role in regulating NSAID-related enteropathy. Dexamethasone aggravated ibuprofen-induced intestinal toxicity l injury .Protease inhibitor therapy in AIDS patients increases their risk of cardiovascular disease, and they routinely use aspirin for prophylaxis. However, the protease inhibitor ritonavir increased aspirin-induced intestinal mucosal injury without increasing gastric mucosal injury .In summary, Indomethacin and diclofenac are more widely used drugs in the current NSAID-induced small intestinal injury model. NSAIDs’ systemic and local effects trigger the development and persistence of small intestinal inflammation in rodents. NSAID-related enteropathy results from multiple factors that complement each other, we have summarized the pathogenetic factors in in vivo animal models or in vitro human cell line models. The latest study reports that enterocyte-like cells derived from human embryonic stem cells are consistent with human cell line trends in toxicological reactions. They have a better correlation with in vivo models (Regarding the construction of disease models, most experiments use o models . They maMany older people have common underlying diseases such as hypertension and diabetes. These patients need to take a certain number of drugs every day. The liver is the principal organ of drug metabolism. Efforts should be made to avoid the use of other drugs that increase liver drug metabolism to improve NSAID-associated intestinal injury. Therefore, the application of dietary therapy and chemically modified NSAID derivatives are promising.Many natural products have anti-inflammatory and antioxidant properties, and they have had some success in treating NSAID-related enteropathy. Besides, natural products have fewer side effects, low cost, and high availability, so the development of such drugs is also promising in the future.Future studies can focus on drug interactions for NSAID-induced intestinal injury and establish guidelines to guide clinical prescription to circumvent the risk of increased harm following drug interactions.


The design of zirconia-based scaffolds using conventional techniques for bone-regeneration applications has been studied extensively. Similar to dental applications, the use of three-dimensional (3D) zirconia-based ceramics for bone tissue engineering (BTE) has recently attracted considerable attention because of their high mechanical strength and biocompatibility. However, techniques to fabricate zirconia-based scaffolds for bone regeneration are in a stage of infancy. Hence, the biological activities of zirconia-based ceramics for bone-regeneration applications have not been fully investigated, in contrast to the well-established calcium phosphate-based ceramics for bone-regeneration applications. This paper outlines recent research developments and challenges concerning numerous three-dimensional (3D) zirconia-based scaffolds and reviews the associated fundamental fabrication techniques, key 3D fabrication developments and practical encounters to identify the optimal 3D fabrication technique for obtaining 3D zirconia-based scaffolds suitable for real-world applications. This review mainly summarized the articles that focused on in vitro and in vivo studies along with the fundamental mechanical characterizations on the 3D zirconia-based scaffolds. Th. Th91]. In contrast, Zhang et al., fabricated a porous zirconia toughened HA composite scaffold for bone-tissue engineering using the DLP 3D-printing process with HA as the primary ratio of the scaffold; additionally, a small amount of zirconia was used as a structural stabiliser . The cer3) porous scaffold (CaSiO3/nano-zirconia scaffold) via the SLS technique for bone-recreation applications with improved mechanical properties [3/nano-zirconia (20%) scaffolds had the ability to mock bone features by forming a bone-like apatite layer and promoting superior assembly of MG-63 cells. The authors concluded that the porous scaffolds with the addition of 20% of nano-zirconia exhibited good biocompatibility and mechanical properties.SLS is a well-established additive-manufacturing technique that employs laser energy as a primary source to fuse powder particles into the desired 3D architecture . It has operties . The autElectrospinning is a unique method in which an electric field induced by a high direct-current voltage between a roller connection and a needle tip is used to spin bioceramic fibers with a constant diameter into an interconnected flexible bioceramic scaffold ,95,96. WThe interwoven PCL/zirconia composite nanofiber scaffolds fabricated by the author had high material stability and porosity, which are favourable for imitating the dynamic atmosphere of natural tissues. Compared with the pristine PCL scaffold, PCL/zirconia composite nanofiber scaffolds exhibited controlled degradation, swelling and superior bioactivity. Additionally, the PCL/zirconia composite nanofiber scaffolds were nontoxic, as indicated by a cell-viability test using the 3T3 mouse fibroblast cell line. This study further confirmed that electrospinning can be used to fabricate PCL/zirconia composite nanofiber scaffolds that are favourable for tissue-engineering.Additionally, Esfahani et al., conducted electrospinning of polyamide 6(PA6)/HA on the surface of the ZTA nanocomposites with improved bioactivity suitable for bone-repair applications . Even thIn contrast to the foregoing replica techniques, Feng et al., designed an acrylonitrile butadiene styrene (ABS) template with organised channel openings using a 3D Rapid Prototyper to construct zirconia scaffolds with different shapes  and porosities . The autSapkal et al., developed a biocomposite scaffold by infusing 10%, 20%, 30%, 40% and 50% zirconia with a β-TCP background via an indirect casting technique. The ABS was first printed using a conventional 3D printer, followed by the impregnation of a zirconia/β-TCP ceramic slurry and subsequent annealing to obtain a zirconia/β-TCP bioceramic scaffold. Osteosarcoma cell line (MG-63) results and compressive-testing results for a sample with a zirconia content of 30% indicated that it was suitable for bone-tissue engineering. Scaffold fabrication with proper porosities suitable for cortical and cancellous bone must be verified .In the aforementioned studies, the direct fabrication of flexible zirconia-containing composite scaffolds via electrospinning was demonstrated. However, a pioneering methodology combining the traditional sponge replica and modern electrospinning methods for fabricating an artificial small bone was reported by Lee et al., in 2011 . ZirconiRecently, Sakthiabirami et al., fabricated porous zirconia 3D scaffolds via FDM . The scaA summary of the zirconia-based scaffolds discussed in the previous sections that have been used for bone-regeneration applications over the past two decades is presented in 2 and its composite materials [Very recently, Weng et.al summarized the properties and construction of ZrOaterials . MoreoveThe non-degradability of zirconia-based scaffolds is a major bottleneck of zirconia-based in comparison with other calcium phosphate bioceramics-based bone-tissue engineering applications. Considerable research attention has been directed toward resolving this concern, and zirconia-based scaffolds have seen advancements over the decades owing to the repeated efforts of bone-tissue engineers. The successful long-term use of zirconia-based implants in dental applications has been validated via clinical trials with 90% survival rates. Even though zirconia-based ceramics are found to undergo fracture in the earlier stage, the absence of surplus parasitic reactions indicates that zirconia can cause no harm to the surrounding biological environments. Hence, zirconia-based scaffolds with 3D porous architectures can provide sufficient osteointegration; once, the bone-remodelling initiated earlier fracture will not be a major issue.In this paper, we comprehensively reviewed the evolution of 3D zirconia-based scaffolds over the years, detailing different fabrication techniques, e.g., the conventional foam replica technique and modern 3D-printing methods. As indicated by the pie chart in In the design aspects, pursuing the finest scaffold design for bone-repair applications has greatly increased; the recent evolution of 3D-printing techniques for designing 3D bioceramic scaffolds has encouraged bone-tissue engineers to construct 3D zirconia-based scaffolds with precise dimensions and interconnected porosity. Even though 3D printing is well established for calcium-based bioceramics aimed for bone-tissue engineering, few studies have been performed on 3D-printing techniques, including extrusion-based, DIW, DLP and SLS techniques, for fabricating zirconia-based scaffolds for bone-tissue engineering. This clearly indicates that 3D-printing techniques are still in a stage of infancy. Among the few studies reported thus far, a multi-extrusion technique-derived 3D zirconia-based scaffold exhibited considerable promise, with improved mechanical and biological properties. However, the surfactants, organic solvents and binders used for the 3D-printing process must be carefully selected, as they can be harmful to host cells and tissues. Given the limited number of reports on zirconia-based scaffolds fabricated via 3D-printing techniques, it may be challenging for future bone-tissue researchers to clearly understand the degradation, mechanical stability and bone-regeneration ability of 3D-printed zirconia scaffolds in load-bearing applications in human biological environments.To address the poor interfacial compatibility between the zirconia scaffolds and incoming cells, three main strategies have been employed by bone-tissue engineers: surface reformation, interface-phase introduction and crystal-structure variation . For insFinally, it is essential to discuss the clinical possibilities of zirconia-based scaffolds. The direct comparison of the strength of the zirconia-based scaffolds to the strength of the natural bone  lacks among the reviewed articles, which is very essential to understand the ability of zirconia-based scaffolds to satisfy the critical bone defects requirements. In most of the collected literature, the in vitro studies focused on validating the metabolic activity of osteogenic cells b. SurpriFew 3D scaffolding technologies have been commercially available, among which CAD/CAM is commonly used and the most dependable. After the successful fabrication of zirconia-based scaffolds for dental applications using the CAD/CAM technique. Apart from the in vitro and in vivo performance, 3D zirconia-based scaffolds fabricated using the CAD/CAM technique has been successfully employed for human mandibular reconstruction. Even though 3D-printed zirconia-based scaffolds were claimed to be the best possible alternatives to the conventional technologies, few in vivo studies support the clinical possibilities of 3D-printed zirconia-based scaffolds. Hence, it is essential to closely monitor the in-depth reproduction of natural mechanical and biological inducements and the rate of vascularisation of 3D-printed zirconia-based scaffolds in the in vivo environment. Multifaceted research should be targeted to systematically appreciate the perspective of 3D printing in bone-restoration applications.The primary goal of the scaffold is to get completely absorbed and replaced by body tissue. However, in large defects, scaffold or implanted artificial bone materials like HA or TCP are not absorbed completely and remained for a long time in vivo studies. And the healing period of each bone is different from several weeks to several months (ex. Femur 6 months). Until now researchers are not able to control the absorption rate of scaffold depending on new bone formation. Over the past 20 years, the zirconia-based scaffold has played a substantial role in critical-sized bone-defect applications, following the tremendous success of modern restorative dentistry. For the large sized loading area, a zirconia-based scaffold that has comparable strength to that of natural bone is needed to support bone formation during the long healing time. However, it remains challenging for orthopaedic experts and bone-tissue researchers to heal critical-sized bone deficiencies using zirconia-based scaffolds, owing to the immature fabrication techniques and unfavourable composite/coating materials for enhancing the bioactivity. Clinically feasible possibilities for promoting surface activation, along with appropriate 3D fabrication practices, are likely to be a focus area for future zirconia-based -scaffold design. The advancements in material engineering in association with biomechanical engineering could be critical in determining zirconia-based scaffolds as a successful biomaterial. Undoubtedly, with the expansion of advanced 3D-printing technology and unique coating strategies, the liability of zirconia-based scaffolds for critical-sized bone-replacement applications is not far away.


The initial response of immune cells against respiratory viruses often determines the severity and duration of disease. The early trajectory of the immune response during infection with SARS-CoV-2 remains poorly understood. Dysregulation of innate immune factors that facilitate viral clearance and the adaptive response, such as type I interferons, have been implicated in severe COVID-19. However, collection of biological samples during the first seven days post-symptom onset has posed a logistical challenge, limiting our knowledge surrounding the immune responses that drive protection versus immunopathology.From March 2020, Military Health System beneficiaries presenting with a positive SARS-CoV-2 test, a COVID-19 like illness, or a high-risk SARS-CoV-2 exposure at nine military medical treatment facilities across the United States were eligible for enrollment in our longitudinal cohort study, which included collection of respiratory sample, sera, plasma, and peripheral blood mononuclear cells (PBMCs). Twenty-five SARS-CoV-2 infected study participants provided samples with in the first seven days of symptom onset, fifteen of whom were hospitalized with COVID-19. We employed multiparameter spectral flow cytometry to comprehensively analyze the early trajectory of the innate and adaptive immune responses.We discovered that early activation of critical antigen presenting cell subsets was impaired upon comparing inpatients with outpatients, correlating with decreased antigen-experienced T cell responses. Specifically, we noted reduced expression of key costimulatory molecules, CD80 and CD86, on conventional dendritic cells that are required for viral antigen-specific T cell priming. Reduction in CD38, a marker of activation was also observed on inpatient dendritic cell subsets.Reduced antigen presenting cell activation and expression of ligands that facilitate T cell engagement may impede the efficient clearance of SARS-CoV-2, coinciding with more severe disease in our cohort. Further analysis of the functional activation of early innate immune responses triggered by SARS-CoV-2 may unveil new immune biomarkers and therapeutic targets to predict and prevent severe disease associated with inadequate T cell immunity.Simon Pollett, MBBS, Astra Zeneca )


Online education offers care providers flexibility and convenience. Applying the New World Kirkpatrick Model of training evaluation, this descriptive study evaluated the design and content of a 30-40 minute online training course that introduces direct-care workers to a multi-sensory device to help manage dementia symptoms in older adults. Following course completion, an online survey obtained ratings of engagement , relevance, and knowledge/skills gained from the training using a 5-point Likert scale. A convenience sample of 72 undergraduate students enrolled in health science and human service programs at a Midwestern university participated. The majority were white (83.3%), non-Hispanic (81.9%) females (88.9%). Most participants agreed or strongly agreed (median=4) with positive statements related to engagement with the course. Statements about relevance to their intended career were rated even higher (median=5). Wilcoxon signed-rank tests for matched pairs revealed statistically significant improvements on self-reported pre-post knowledge/skills scores (p<0.005). The results indicated that participants found the training aesthetically pleasing, easy to use, novel, and that it encouraged user involvement. Participants thought the topics covered were relevant to the professional career they are pursing, and they learned new knowledge/skills. Responses to open-ended questions suggested improvements to the design  and content . Future research will evaluate a revised course with direct-care workers who will use the multi-sensory device in long term care facilities. Subsequently, an intervention study will determine the effectiveness of the device in increasing the well-being of people with dementia.


MicroRNAs (miRNAs) are diminutive noncoding RNAs that can influence disease development and progression by post-transcriptionally regulating gene expression. The anti-inflammatory miRNA, miR-223, was first identified as a regulator of myelopoietic differentiation in 2003. This miR-223 exhibits multiple regulatory functions in the immune response, and abnormal expression of miR-223 is shown to be associated with multiple infectious diseases, including viral hepatitis, human immunodeficiency virus type 1 (HIV-1), and tuberculosis (TB) by influencing neutrophil infiltration, macrophage function, dendritic cell (DC) maturation and inflammasome activation. This review summarizes the current understanding of miR-223 physiopathology and highlights the molecular mechanism by which miR-223 regulates immune responses to infectious diseases and how it may be targeted for diagnosis and treatment. MicroRNAs (miRNAs) are small, non-coding RNAs comprising 20–25 nucleotides that play a critical role in post-transcriptional regulation of gene expression by binding target messenger RNA (mRNA) –3. As a MiRNAs are encoded by miRNA genes with the help of miRNA enzymes and tightly controlled by cellular localization. While many miRNAs exist in different tissues and cells, biosynthesis and maturation follow a similar process. MiRNAs are initially transcribed in the cell nucleus as long primary miRNAs (pri-miRNAs) with the help of RNA polymerase II . Pri-miRMiRNAs are strong regulators of physiological processes such as organ development and metabolism, tissue repair and remodeling, and cell growth and differentiation by cleaving mRNAs and/or preventing gene expression . MiRNA cInterestingly, miRNAs can also induce target gene expression by regulating transcription or translation. In 2008, Place et al.  reportedMiR-233 exists on the X chromosome protein, is highly expresses in the myeloid lineage, and plays a critical role in myeloid cell differentiation . This gePeroxisome proliferator-activated receptor γ (PPARγ), a nuclear transcription factor, is also a key miR-223 transcription factor in macrophages. PPARγ controls miR-223 expression by directly linking to PPARγ regulatory elements (PPREs) located on the pre-miR-223 promoter and inducing M2 activation . In contEpigenetic mechanisms are changes in gene expression based on non-sequence alterations such as DNA methylation and chromatin conformational changes. As miRNAs are generated, epigenetic mechanisms play a critical role in miRNA expression. Common acute myeloid leukemia-associated fusion protein, AML1/ETO oncoprotein, prevents miR-223 expression by recruiting histone deacetylase (HDAC) and DNA methyltransferases to the pre-miR-223 gene and causes leukemia pathogenesis . EpigeneMiR-223 is highly expressed in the hematopoietic system and is an important modulator of hematopoietic differentiation by orchestrating expression of hematopoietic stem cells, erythroid cells, and granulocyte-monocyte progenitors at different stages of development . Studies-/Y mouse model and granulocyte numbers were increased. Lack of miR-223 induced Mef2c expression, a transcription factor that promoted proliferation of granulocyte-monocyte progenitors. Indeed, in miR-223-/Y animals, the specific knockout of Mef2c in myeloid cells, resulted in normal granulocyte numbers  expression increases as differentiation occurs. This results in higher IKK-α protein expression, which induces p52 and impairs NF-κB signaling pathways . Additio+ve cells) to differentiate into macrophages (Another study found that miR-223 expression was downregulated during macrophage differentiation. Lower levels of miR-223 were found to increase nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) expression, which helps primary human monocytes . In K562 cells, an erythroid–megakaryocyte cell line, researchers found that miR-223 exhibited a powerful ability to inhibit erythroid cells and promote megakaryocyte differentiation , 56. A kMiR-223 is a critical regulatory element for eosinophil development by influencing the proliferation and differentiation of eosinophil progenitor cells. Studies show that upregulation of miR-223 induces eosinophil differentiation by promoting expression of insulin-like growth factor-1 receptor (IGF-1R). More importantly, ablation of the miR-223 gene in eosinophil progenitors resulted in an increased number of eosinophil progenitors and a delay in differentiation . MiR-223via several pathways. DCs develop from hematopoietic stem cells (HSCs) and are major antigen-presenting cells that capture and present antigen to T lymphocytes. DC development is a complicated process regulated by several factors  during differentiation of ES cells into DCs  macrophages associated with AT inflammation, which leads to severe insulin resistance and AT disorder. MiR-223 induces macrophages towards the alternative M2 phenotype by suppressing Pknox1 expression, which improves macrophage-mediated AT inflammation and insulin resistance. A role for miR-223-induced Pknox1 expression was also shown in the coxsackievirus B3 (CVB3)-induced viral myocarditis mice model  inflammation . MiR-223ce model . In CVB3ce model .Research has also shown that miR-223 has a powerful ability to regulate macrophage polarization. The nuclear transcription factor, PPARγ, binds directly to the pre-miR-223 promoter and induces miR-223 gene expression. Macrophages are then polarized towards an alternative M2 anti-inflammatory phenotype by targeting Rasa1 and NFAT5 . A separH. pylori-infected macrophages. Over expression of microRNA-223 reduced NF-kB activation and TNF-α, IL-6 and IL-1β production by inhibiting IRAK-1 in H. pylori-infected macrophages  . Interesrophages . In addirophages . In muri-/y mice model , an increased ratio of lung wet-to-dry weight ratio, and more cells infiltrating the airway. Overexpression of miR-223 reversed those symptoms by reducing Ly6G+ neutrophil numbers and inhibiting NLRP3 inflammasome activity  mice model, a high level of miR-223 was observed, helping to alleviate neutrophil activation and mitigate liver injury . During ammation .In summary, miR-223 appears to be abundant in neutrophils, serving to inhibit neutrophil activation and function during inflammatory diseases. Thus, miR-223- mediated neutrophil activation may be a target for treatments aimed at reducing neutrophil-driven inflammation to prevent hyperactive immune responses.DCs are potent antigen-presenting cells that play a pivotal role in inducing and maintaining tolerance and immunity . In resp+ T cell development. These data indicate that miR-223 is a negative regulator of LCs cross-presentation capacity, however the mechanism by which this occurs is not fully understood. MiR-223 was also found to regulate DC differentiation and function during colitis by directly targeting C/EBP-β , skin-residential dendritic cells . High mi C/EBP-β . Indeed,in vitro  . In an Ein vitro . Howeverin vitro , 84.-/-) mice with EAE exhibited lower central nervous system (CNS) autoimmune inflammation and less pro-inflammatory APC infiltration than wild-type mice. Basal and LPS-induced IL-12 and IL-23 levels were also lower in DCs from miR223-/- mice than wild-type mice. These results appear to contrast with studies indicating that miR-223 inhibits DC activation. It is evident that miR-223 plays a key role during cellular development, particularly in myeloid differentiation and immune cell development and function. Studies show that miR-223 levels vary between different stages of bone marrow cell development. MiR-223 deficiency impairs the development of bone marrow derived cells and inhibits DC function  are specifically recognized by host innate pattern recognition receptors (PRRs), including TLRs, nucleotide-binding domain leucine-rich repeat-containing proteins (NLRs), and C-type lectins . This prHelicobacter pylori (H. pylori) infection, and sepsis, helping to maintain equilibrium between protective immune responses and host injury caused by excessive inflammation  are the most common causes and are aptly named after the clinical disease. These viruses primarily infect and damage hepatocyte function, and also activate immune cells like macrophages, neutrophils, and T cells, resulting in a cascade of liver inflammation . MiR-223MiR-223 expression is also associated with HCV infection and positive treatment outcomes in humans. Low miR-223 levels were observed in HCV patient serum, while high miR-223 levels were obtained from patients who had reached sustained virologic response (SVR) after treatment. These data indicate that miR-223 levels may show that miRNAs have performed an antiviral function during SVR and/or physiological response to viral clearance. Findings also suggest that different levels of circulating miR-223 correlate with the therapeutic effect and pathological features of liver disease . A profiIn addition to regulating the early stage of viral infection, miR-223 is also involved in HBV/HCV-related liver fibrosis. Study shows that miR-223 levels are significantly different in serum from HCV-related liver fibrosis patients than healthy people, and may be used as a new non-invasive diagnostic and prognostic marker of HCV-induced liver cirrhosis . MiR-223Hepatic fibrosis is a complex and multifactorial pathophysiological progress that is closely linked to chronic inflammatory injury, impairing the balance between production and dissolution of the extracellular matrix . It is uAll of these findings together indicate that miR-223 not only acts as a biomarker but also performs a key role in the pathophysiological progression of viral hepatitis. It is likely to inhibit inflammatory responses caused by hepatitis viruses, supporting the finding that low miR-223 levels are usually associated with chronic inflammatory disorders in the liver. However, the mechanism by which miR-223 controls immune cell activation and regulates hepatitis virus-induced inflammation remains unclear.HIV-1, which primarily infects immune cells, in particular T lymphocytes , is identified as the causative agent of acquired immunodeficiency syndrome (AIDS), which leads to opportunistic infections and diseases , 99. HIVResearch shows that macrophages stimulated with IFN-α and IFN-β express high levels of miR-223, indicating that this is one of the mechanisms by which macrophages launch an antiviral response . A highe+T lymphocytes and interferon-γ, are most critical (TB is a chronic disease primarily caused by the mycobacterium TB (MTB) and characterized by long-term fever, dreaminess, expectoration, and emaciation. Bacterial quantity and toxicity, as well as host immune function, play important roles in mediating the occurrence, progression, and prognosis of TB. Dynamic regulation of innate immunity is recognized as a decisive factor in protecting the host from mycobacteria. It is shown that the close cooperation between cytokines and immune cells is essential to anti-TB immunity, of which macrophages, effector CD4critical . ConsideRecent evidence shows that miR-223 plays an essential part in regulating innate host responses to mycobacterial infection. Earlier studies showed that miR-223 was differentially expressed in the peripheral blood mononuclear cells (PBMCs) of active and latent TB patients, suggesting that miR-223 may regulate TB progression . Blood aMTB is phagocytosed by and replicates in macrophages following entry into the body. Evidence shows that virulent MTB causes widespread infection by preventing macrophage apoptosis and allowing persistent replication . Thus, mIn summary, miR-223 is closely associated with the host immune response to MTB. Several studies have defined the regulatory features of miR-223, which appear to interrupt MTB replication and maintain the host’s innate immune. This suggests that miR-223 may be a novel target for MTB treatment. Understanding the mechanism by which miR-223 mediates the immune response to MTB will inform miRNA-based approaches for host-directed therapeutics and vaccines against MTB infections. MiR-22 may also serve as a much-needed biomarker for diagnosing TB and assessing disease progression.H. pylori, a common bacterium existing in the stomach of half the world’s population, can infect the gastric epithelium and cause chronic gastritis, characterized by high neutrophil and mononuclear cell numbers in the lamina propria  and found to play an essential role in maintaining the balance of innate immunity to avoid excessive inflammation and tissue injury. In addition, miR-223 is involved in inhibiting virus replication and regulating inflammation-induced carcinogenesis.Considering its important role in mediating immune cell function and infectious pathophysiology, miR-223 is identified as a promising biomarker and therapeutic tool for the diagnosis and therapy of infectious diseases. However, further investigation is needed to verify the accuracy, reliability, and prognostic and therapeutic potential of miR-223. First, circulating miR-223 has distinct expression profiles during different infectious diseases, indicating that large-sample clinical studies are required to further determine its ability to accurately diagnose infection. In addition, miR-223 not only regulates gene expression in an intracellular manner to mediate myeloid cell responses to infection but can also be processed into exosomes and used as an intercellular communication tool. Thus, miR-223-based therapy using miR-223 analogues or cells expressing high levels of miR-223 may be an exciting option for infectious disease treatment. Future studies should assess how to selectively and accurately target miR-223-derived drugs to infection sites. In addition, the safety and efficacy of miR-223-based treatment need to be further evaluated in larger animals and clinical trials. Finally, studies must further elucidate potential miR-223 targets and determine how it correlates with irritation and most cancers, improving the current understanding of miR-223 biology and contributing to safer and more precise treatment for infectious diseases.In summary, while already used as a biomarker in numerous inflammatory disorders, the precise mechanism and therapeutic capacity of miR-223 should be explored more comprehensively to assess how it may be used to improve treatments for a wide range of inflammatory disorders.Designed and wrote the manuscript: SY and QW. Revised the content: YYC and SZ. Modified the language: XZ and FS. Draw the images: YJC. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (Grant No.81570428), Key Support Project of Health Commission of Hubei Province (Grant No. WJ2019Z012), and Guiding Fund of Renmin Hospital of Wuhan University (Grant No. RMYD2018Z07).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), rapidly became a global health challenge, leading to unprecedented social and economic consequences. The mechanisms behind the pathogenesis of SARS-CoV-2 are both unique and complex. Omics-scale studies are emerging rapidly and offer a tremendous potential to unravel the puzzle of SARS-CoV-2 pathobiology, as well as moving forward with diagnostics, potential drug targets, risk stratification, therapeutic responses, vaccine development and therapeutic innovation. This review summarizes various aspects of understanding multiomics integration-based molecular characterizations of COVID-19, which to date include the integration of transcriptomics, proteomics, genomics, lipidomics, immunomics and metabolomics to explore virus targets and developing suitable therapeutic solutions through systems biology tools. Furthermore, this review also covers an abridgment of omics investigations related to disease pathogenesis and virulence, the role of host genetic variation and a broad array of immune and inflammatory phenotypes contributing to understanding COVID-19 traits. Insights into this review, which combines existing strategies and multiomics integration profiling, may help further advance our knowledge of COVID-19. Coronavirus disease 2019 (COVID-19) was first detected in China in December 2019, and was subsequently declared a global pandemic by the World Health Organization in March 2020 . Severe Despite the rapid global scientific response to COVID-19, disease management and scientific research remain emergency-level challenges. Evidence indicates that both viral and host factors play critical roles in COVID-19, with host factors closely impacting disease severity , 19. MulA striking feature of COVID-19 is its heterogeneity , involviAn integrated approach to investigations of SARS-CoV-2 could facilitate the study of complex biological processes holistically, while the integration of multiomics data highlights the interrelationships amongst the involved biomolecules and their functions . As an uIdentifying the characteristics of COVID-19 strains helps better understand the virus’ successful invasion and transmission, potentially aiding an understanding of the population-specific variations leading to a high rate of SARS-CoV-2 infections . For exaCompared to single omics research in COVID-19, integrated proteome, transcriptome, interactome and bibliome data from COVID-19 research details the biological factors associated with SARS-CoV-2 infection, including more enriched processes such as neutrophil degranulation in the virus . For insThe clinical presentation of COVID-19 consists of asymptomatic and symptomatic patients, but asymptomatic patients present with positive detections of the nucleic acid of SARS-CoV-2 and can transmit the virus to others . A previThe clinical course of COVID-19 infection is highly variable in severity, initially falling into four types: mild, moderate, severe and critical . MultiplHypertension, cardiovascular diseases (CVDs), diabetes mellitus chronic kidney diseases (CKDs), cancers and chronic obstructive pulmonary disease (COPD) are common comorbidities or pre-existing conditions in COVID-19 associated with worse outcomes , 51–53. Multiomics integration data could be used to determine a biosignature to identify COVID-19 progression, prognostics and predicting outcomes amongst heterogeneous patients and guide therapeutic interventions. For example, multiomics profiles revealed that features of the stages of seroconversion could be used to stratify COVID-19 patients and correlate with different pathophysiological states, involving multiple underlying pathophysiological processes such as hyperinflammation and thrombotic microangiopathy . Low antDespite multiple vaccines being widely and globally deployed, the pandemic continues to progress, and effective treatment remains largely unavailable. One of the primary purposes of understanding the characteristics of COVID-19 through multiomics integration data is to accelerate the development of drugs, vaccines, prevention tools and therapies for COVID-19. Multiomics data suggest that a high-frequency amino acid variation (AAV) in mutations could be considered for the novel design of a vaccine , whilst Mounting evidence suggests that symptoms may last for months after recovery from the initial COVID-19 infection . Whilst The development of multiomics integration bioinformatics approaches has provided an opportunity to comprehensively understand a complex disease involving multiple molecular-level changes and their interactions, representing an important direction in systems and precision medicine. In previous reviews, these approaches could be grouped based on their purpose: disease subtyping and patient stratification; diagnostic and prognostic predictive model construction; and driving insight into disease biology through the identification of biomarkers, pathways and disease networks . Such apMultivariate analyses such as partial least squares (PLS) and its extension multi-block PLS are supervised multivariate analyses seeking predictable features and attempting to build predictive models for both the severity and outcomes of COVID-19. Liu et al.  built a Machine learning approaches have a higher potential to construct efficient predictive models for complex and ambiguous data. Specifically, such approaches could be used in unsupervised COVID-19 subtyping and patient stratification, and in constructing supervised diagnostic and prognostic predictive models. For instance, Overmyer et al.  construcNetwork-based integration approaches have been increasingly applied in multiomics COVID-19 research given that such approaches match the nature of multilevel, complex and crosstalk interaction networks involved in SARS-CoV-2 infection and COVID-19 disease progression. Network approaches could illustrate and explain interactions amongst multilevel molecules, including DNA, RNA, protein, metabolites and their interactomes, as well as cellular interactions and immune responses across all processes from SARS-CoV-2 exposure to COVID-19 disease and post-COVID syndrome. Terracciano et al.  utilizedMultistaged sequential approaches are typically used to integrate parallel analyses from each single-omics or layer of data. One method involves identifying differentially expressed signatures or genes from each single-omics platform, then merging these lists based on their direct overlap or further enriched downstream functions or pathways. For example, Chen et al.  identifiThe similarity between molecular changes and drug responses from a diseasome view relies on the basic premise of similarity or correlation-based analysis in COVID-19. For instance, Overmyer et al.  performeCOVID-19 represents a challenging emergency both in terms of disease management and scientific research. Multiomics integration molecular characterization of COVID-19 patients will greatly assist preventive and personalized medicine efforts. In our review of 32 multiomics studies on COVID-19 published before July 2021 featuring at least two integrated omics datasets, we identified some trends and challenges in multiomics research on COVID-19.Similarity-based assumptions, ranging from virus and disease phenotype to drug response correlation at the multiomics level, represent one fundamental hypothesis, which applies previous knowledge to COVID-19 research see . BrieflyMore than ten different kinds of omics or molecular signatures from over 15 biospecimen types have been used in the 32 multiomics studies discussed in this review  resulting from very strict exclusion criteria in terms of co-morbidities, treatments, etc. [In this review, we discuss the current status of and potential for multiomics integration in COVID-19 research. The investigations performed to date primarily focused on predicting SARS-CoV-2 infection and COVID-19 severity. However, in order to harness the full potential of multiomics investigations, great care must be places on the study- and cohort design. We have previously shown that multiomics integration can increase the statistical power to classify small sub-groups of patients greatly, reducing the required group size to reach 95% power from ts, etc. . In conthttps://opendata.ncats.nih.gov/covid19/omics), as well as analytical and visualization tools, which are friendly for non-bioinformaticians. These tools help to quickly apply results and make available original data to the clinical and research communities. Given the diversity and complexity of multiomics, we found many studies associated with several databases or resources, along with varying depths of procession. Well-processed data in an integrated, standardized format will benefit the re-analysis and re-integration of data. Thus, we developed an online Shiny App termed ‘Collection of multiomics datasets in COVID-19’ (available via https://zhougroup.shinyapps.io/moCOVID/) to aid researchers and clinicians in searching COVID-related multiomics investigations , etc., experienced by patients with PACS. Identification of the molecular characteristics of this broad range of COVID-19 patients, powered by multiomics integration studies could offer a tremendous potential to unravel SARS-CoV-2 pathobiology, disease progression and resolution, predicting outcomes, prevention and therapy. Many lessons learned from multiomics integration in like various cancer types and respiratory disease can potentially transfer to COVID-19 research , 66, 67.An increased and comprehensive understanding of COVID-19 characteristics is crucial to guiding the pandemic response.Identification of the molecular characteristics of COVID-19 patients from multiomics integration studies offers tremendous potential to unravel the puzzles related to SARS-CoV-2 pathobiology and COVID-19 progression.Multiomics integration-based molecular characterizations of COVID-19 could answer multiple important questions, specifically those related to disease severity, outcome prediction, prevention and therapy.To date, more than ten types of omics data and five categories of multiomics integration approaches have been applied to COVID-19 research, with further research potential and challenges in the biological and bioinformatics areas.BIB-21-1083_R1_suppl_table1_1110_bbab485Click here for additional data file.BIB-21-1083_R1_table2-4_1004_bbab485Click here for additional data file.