Recent medical advancements have strived for a personalized medicine approach to patients, aimed at optimizing therapy outcomes with minimum toxicity. In this respect, nuclear medicine methodologies have been playing increasingly important roles. For example, the overexpression of peptide receptors, such as the gastrin-releasing peptide receptor (GRPR), on tumor cells as opposed to their lack of expression in healthy surrounding tissues can be elegantly exploited with the aid of “smart” peptide carriers, such as the analogs of the amphibian 14-peptide bombesin (BBN). These molecules can bring clinically attractive radionuclides to malignant lesions in prostate, breast, and other human cancers, sparing healthy tissues. Depending upon the radionuclide in question, diagnostic imaging with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) has been pursued, identifying patients who are eligible for peptide radionuclide receptor therapy (PRRT) in an integrated “theranostic” approach. In the present review, we (i) discuss the major steps taken in the development of anti-GRPR theranostic radioligands, with a focus on those selected for clinical testing; (ii) comment on the present status in this field of research; and (iii) reflect on the current limitations as well as on new opportunities for their broader and more successful clinical applications.The gastrin-releasing peptide receptor (GRPR) is expressed in high numbers in a variety of human tumors, including the frequently occurring prostate and breast cancers, and therefore provides the rationale for directing diagnostic or therapeutic radionuclides on cancer lesions after administration of anti-GRPR peptide analogs. This concept has been initially explored with analogs of the frog 14-peptide bombesin, suitably modified at the N-terminus with a number of radiometal chelates. Radiotracers that were selected for clinical testing revealed inherent problems associated with these GRPR agonists, related to low metabolic stability, unfavorable abdominal accumulation, and adverse effects. A shift toward GRPR antagonists soon followed, with safer analogs becoming available, whereby, metabolic stability and background clearance issues were gradually improved. Clinical testing of three main major antagonist types led to promising outcomes, but at the same time brought to light several limitations of this concept, partly related to the variation of GRPR expression levels across cancer types, stages, previous treatments, and other factors. Currently, these parameters are being rigorously addressed by cell biologists, chemists, nuclear medicine physicians, and other discipline practitioners in a common effort to make available more effective and safe state-of-the-art molecular tools to combat GRPR-positive tumors. In the present review, we present the background, current status, and future perspectives of this endeavor. Bombina bombina and exerting a series of actions on mammal tissues through binding to distinct G-protein coupled receptors (GPCRs), known as bombesin receptors (BB-Rs) Tc-RP527 ), whereby, the N3S donor atom set, attached at the N-terminus via a Gly-5-aminovaleric acid linker, was used for binding Tc-99m under formation of a stable, neutral [99mTc]TcVO(N3S) complex in square pyramidal configuration Tc-based radiotracers rapidly through the kidneys into urine to minimize radioactivity levels in the abdomen could be promoted by using hydrophilic metal chelates. For such purposes, open chain tetraamines were soon coupled at the N-terminus of bombesin analogs directly or via different linkers. Acyclic tetraamines wrap around the trans-[99mTc]TcV(O)2+ core at the equatorial plane of an octahedron forming monocationic hydrophilic trans-[[99mTc]TcV(O)2(N4)]+ complexes BBN affording DB4. The forming hydrophilic radioligand [99mTc]Tc-DB4 showed swift and high localization in human prostate cancer PC-3 xenografts in mice combined with a rapid background clearance predominantly via the kidneys [99mTc]Tc-DB4 successfully imaged primary prostate cancer on SPECT/CT in therapy-naive patients, but had limited efficacy in visualizing pathological lesions in more advanced hormone refractory prostate cancer patients Lu-AMBA was first reported to show high therapeutic potential in several prostate cancer models having different GRPR expression levels, namely based on PC-3, LnCaP, and DU145 cells [213Bi]Bi-AMBA was studied and compared with another bombesin radioligand differing only in the linker and labeled both with Lu-177 and Bi-213, [177Lu]Lu/[213Bi]Bi-DOTA-PESIN ), in PC-3 xenografts Bi-radioligands, a better safety profile for [213Bi]Bi-DOTA-PESIN than for [213Bi]Bi-AMBA. In the PRRT arena, the potent bombesin agonist AMBA (DOTA-Gly-4-aminobenzoyl-BBN(7–14)) has attracted much attention, whereby, the universal chelator DOTA  was coupled to Gln therapy . Accordi45 cells . Furthernografts . The stu68Ga]Ga-AMBA was reported to be tolerated with minor adverse effects , revealing several pathological lesions, especially in breast and prostate cancer patients, and displaying significant uptake mainly in the pancreas and intestinal tract as well as in the esophago-gastric junction [177Lu]Lu-AMBA Lu-AMBA . In conclusion, the application of radiolabeled BBN-like agonists in human, especially during PRRT requiring higher peptide doses administered to patients, has been linked to biosafety hurdles. Although receptor activation following agonist binding triggers internalization of the receptor-(radio)peptide complex into target cells, at the same time severe side effects can be released, predominantly in the gastrointestinal system ,44,45. FSeveral GRPR antagonists have been developed in previous years in order to better understand the pharmacology and roles of bombesin and its receptors in various physiological and pathophysiological conditions. The growth stimulatory effects of bombesin agonists in several human cancers have triggered systematic efforts to develop GRPR antagonists as antitumoral drugs, capable of binding to the receptor with a high affinity without it being activated ,49,50. A2 dipeptide Tc-based radiopharmaceuticals still account for approximately 80% of all nuclear medicine procedures. This radionuclide is widely available in pharmaceutical grade in many hospitals via commercial [98Mo]Mo/[99mTc]Tc-generators, in low-cost and high specific activity and has ideal physical properties with a half-life of 6 h, an optimal energy of 140 keV for imaging with currently used instrumentation combined with low radiation exposure of patients and personnel BBN(6–13), obtained by ethylamidation of C-terminal Leu13 after removal of the last amino acid ([des-Met14]-class of GRPR antagonists) [p-aminomethylaniline-diglycolic acid (AMA-DGA) linker. The forming radioligand [99mTc]Tc-Demobesin 1 ([99mTc]Tc-DB1) was the first radiolabeled GRPR antagonist tested in PC-3 tumor-bearing mice showing excellent and specific receptor targeting properties, combining high accumulation in the experimental tumor with a fast background clearance via the kidneys into urine. Rapid washout was observed even from GRPR-rich organs, such as the pancreas, resulting in improved tumor-to-background ratios over time, a feature characteristic for most GRPR radioantagonists thereafter [99mTc]Tc-DB1 with the agonist-based [99mTc]Tc-DB4, [99mTc]Tc-DB1, despite the lack of internalization, achieved higher tumor uptake and faster washout from GRPR-positive tissues [11-analog [99mTc]Tc-DB15 as a promising candidate for clinical translation [99mTc]Tc-DB15, whereby, the tracer visualized several bone and soft tissue metastases on SPECT/CT, while being well tolerated BBN(6–13), 67Ga]Ga-SB3, serving as a surrogate of [68Ga]Ga-SB3, compared well with [99mTc]Tc-DB1, with regards to tumor uptake and retention and background clearance. [68Ga]Ga-SB3 was selected for clinical testing in a small cohort of patients with disseminated prostate and breast cancers, whereby it was able to visualize lesions in about 50% of the patients on PET/CT [111In]In-SB3 counterpart and the therapeutic [177Lu]Lu-SB3 version were shown to be rapidly catabolized in vivo by neutral endopeptidase. This handicap, compromising their clinical translation perspectives, could be, however, overcome by means of specific inhibitors (vide infra) [111In]In-SB3 administered in combination with such an inhibitor in mice, successfully visualized PC-3 tumors using SPECT/MRI, revealing its potential for preoperative imaging of prostate cancer In-RM1  was developed with DOTA coupled to JMV594 via the same linker used in [111In]In-AMBA to allow for a side-by-side comparison BBN(6–14), 68Ga]Ga-RM2 has been widely studied in different prostate cancer cell lines and tumor models and has shown improved binding affinity to the GRPR and metabolic stability [68Ga]Ga-RM2 was the most clinically tested PET tracer based on this class of GRPR antagonists, studied in a small cohort of healthy volunteers [68Ga]Ga-RM2 was well tolerated by all patients and showed high sensitivity, specificity, and accuracy for the detection of primary cancer. Its feasibility for detecting most metastatic lesions highlights that it has high potential as a diagnostic PET tracer for GRPR-positive tumors. In another approach, NOTA  was attached at the N-terminus of JMV594 either directly or via a PEGx linker, allowing labeling with Ga-68 and the formation of the PET tracer [68Ga]Ga-RM26 , A positive charge at the N-terminus, introduced either by a positively charged linker or by the radiometal chelate per se, turned out to favor GRPR affinity as well as in vivo pharmacokinetics of resulting radioligands ,63,64,65lunteers , breast lunteers , and prolunteers . In thes177Lu]Lu-RM2 has been studied in patients with metastatic castration-resistant prostate cancer, showing promising features for clinical use. Thus, absorbed doses in tumor lesions were found to be therapeutically relevant, whereas rapid clearance from normal GRPR-rich organs was confirmed, such as the pancreas, considered to be the dose-limiting organ due to its high radioligand uptake Tc-N4-AR and [64Cu]Cu-CB-TE2A-AR) in terms of GRPR affinity and tumor uptake and retention. Notably, [64Cu]Cu-CB-TE2A-AR -1,4,8,11-tetraazabicyclo(6.6.2)hexadecane, 64Cu]Cu-CB-TE2A-AR showed long tumor retention and fast clearance from other organs GRP(20–27) motif 2)2) represent a successful class of very potent GRPR antagonists, characterized by high receptor affinity and in vivo enzymatic stability. Accordingly, the GRP(20–25) sequence was modified by DOTA-AMA-DGA at the N-terminus affording NeoBOMB1. NeoBOMB1, labeled with Ga-68 (for PET), In-111 (for SPECT), or Lu-177 (for PRRT) showed promising theranostic profiles during preclinical evaluation, characterized by high receptor affinity and cell-uptake efficiency in vitro together with high metabolic stability and high and prolonged tumor uptake in GRPR-expressing tumors in vivo [68Ga]Ga-NeoBOMB1 in a group of prostate cancer patients highlighted its ability to visualize primary tumors as well as liver metastases and bone lesions  in patients with advanced solid tumors known to overexpress GRPR Ga-BBN-RGD enhancing diagnostic accuracy in breast and prostate cancer patients In-Tz, and thus far, have failed to improve tumor-to-pancreas ratios, most likely due to undesired folding of the targeting vector in the binding pocket of the GRPR Lu-RM2 alone in mice models has been reported to further improve when combined with the mTOR inhibitor rapamycin [177Lu]Lu-RM26 and trastuzumab combination in prostate cancer mice models Ga-RM2 and [68Ga]Ga-PSMA-11 on PET/CT in seven patients with biochemically recurring prostate cancer, shown in GRPR-targeted imaging may constitute a relevant addition for those patients with PSMA-negative tumors, estimated to constitute 74% of patients, or those with low-grade tumors that do not show on MRI nor PSMA PET scans . Indeed,Importantly, GRPR and PSMA expression are both affected by standard of care treatments applied in prostate cancer, including targeting the androgen receptor pathway and taxane-based chemotherapy . Althoug225Ac]Ac-PSMA therapy is already being evaluated in the clinic with promising biochemical responses and low treatment-related toxicity [177Lu]Lu- and [225Ac]Ac-PSMA have been applied that suggest improving PSMA-radiotherapy response while minimizing toxicity of the salivary glands [In addition to their use in diagnostics, PSMA and GRPR hold promise for the application of radionuclide therapy in the management of prostate cancer. Clinical application of this theranostic approach has just started, and reports are still scarce . Althougtoxicity . Finallyy glands . Alternay glands .The fast introduction of PSMA radiotracers for imaging and therapy has radically shifted the clinical perspectives of prostate cancer patients. But clearly, clinical evaluation has just started, and well-designed prospective randomized trials are needed to learn how to use these new applications in daily practice: (1) how to interpret PSMA PET/CT ; (2) how to optimally position PSMA radiotherapy in the sequence of standard of care therapies; and most importantly, (3) how to alleviate radiotoxicity without losing therapeutic efficacy. GRPR-targeted radioligands may help to solve, at least in part, these clinical issues by complementing the PSMA PET/CT and radioligand therapy and improving the prostate cancer detection rate as well as therapeutic efficacy.In view of the above, it becomes evident that research in the field of radiolabeled bombesin analogs for application in the theranostic management of GRPR-positive human tumors has been thriving with major breakthroughs already achieved. Firstly, the paradigm shift from agonist- to antagonist-based radioligands has competently addressed the issue of biosafety, a very crucial point during PRRT with higher peptide amounts administered to patients. Secondly, the challenge of rapid degradation of BBN-like tracers entering the circulation has been “elegantly” met with the application of NEP inhibitors. The latter may be directly applied for in situ stabilization of biodegradable radioligands, but at the same time have been instrumental in a smarter design of metabolically robust analogs. Extended and systematic structure-activity relationship studies have pinpointed candidates eligible for clinical translation in breast, prostate, and other GRPR-positive cancer patients, applying SPECT/CT, or PET/CT imaging and PRRT.Such pioneer clinical studies have been eye-openers with regards to the strengths and limitations of GRPR-positive cancer theranostics, revealing new challenges to be met. Our incomplete understanding of cancer pathology needs to be improved in order to provide solid information on critical issues, such as GRPR expression status in different types and stages of cancer, as well as following previous therapies in cases of advanced disease. This critical knowledge will certainly provide new opportunities for the successful application of multitargeted theranostic agents and, most importantly, of adjuvant therapies. Accordingly, combining PRRT with the aid of anti-GRPR radioligands with other therapies, such as hormone therapy, immunotherapy, and other therapeutic schemes, should be adopted to individual patients, aiming at maximum efficacy and low toxicity. The seeds for these innovative developments have already been planted and will most certainly lead to new exciting breakthroughs in the near future.


A subsequent histological workup determined a sarcoid-like reaction without any lymphomatous tissue. Therefore, sarcoid-like reactions should be considered as a potential pitfall in Deauville staging with 18F-FDG PET/CT imaging for patients with NHL.The sarcoid-like reaction represents an autoinflammatory cause of mediastinal and hilar lymphadenopathy but may also involve other lymph node regions and organs. This rare phenomenon has mainly been reported in patients with Hodgkin’s lymphoma (HL) or solid tumors (particularly melanoma) undergoing immunotherapy and chemotherapy. Cases in non-Hodgkin’s lymphoma (NHL) are very uncommon. We present an uncommon case of a patient with primarily mediastinal diffuse large B-cell lymphoma (DLBCL) who showed a CT-based partial response in interim staging, whereas at end-of-treatment multiple newly enlarged and hypermetabolic mediastinal and bilateral hilar lymph nodes were detected by  The sarcoid-like reaction represents an autoinflammatory cause of mediastinal and hilar lymphadenopathy ,2. This In this case , the occ18F-FDG PET/CT imaging, even in NHL patients and in cases with high metabolic activity.Overall, this case underlines the importance of the tissue biopsy of unclear newly appearing lesions in patients with lymphoma. In clinical routine, sarcoid-like reactions should be considered as a potential pitfall in Deauville staging with


Kidney transplant recipients are at high risk of developing severe COVID-19 due to the coexistence of several transplant-related comorbidities  and chronic immunosuppression. As a consequence, a large part of SARS-CoV-2 infected patients have been managed with a reduction of immunosuppression. The mTOR-I, together with antimetabolites, have been often discontinued in order to minimize the risk of pulmonary toxicity and to antagonize pharmacological interaction with antiviral/anti-inflammatory drugs. However, at our opinion, this therapeutic strategy, although justified in kidney transplant recipients with severe COVID-19, should be carefully evaluated in asymptomatic/paucisymptomatic patients in order to avoid the onset of acute allograft rejections, to potentially exploit the mTOR-I antiviral properties, to reduce proliferation of conventional T lymphocytes (which could mitigate the cytokine storm) and to preserve Treg growth/activity which could reduce the risk of progression to severe disease. In this review, we discuss the current literature regarding the therapeutic potential of mTOR-Is in kidney transplant recipients with COVID-19 with a focus on pulmonary fibrosis. Over the last few months, a large number of kidney transplant recipients worldwide have been diagnosed with COVID-19 , and mosMain reasons for the dramatic negative clinical impact of COVID-19 pandemic on this fragile cohort of patients is the coexistence of suppression of the immune system by anti-rejection drugs  and the Recent reports have suggested that pulmonary fibrosis associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be triggered by both viral- and immune-mediated mechanisms  and exacAdaptive immunity is also activated in COVID-19 patients mainly by antigen presenting dendritic cells, which produce large amounts of cytokines, including interleukin (IL)-6, IL-1β and tumor necrosis factor-alpha (TNF-α) and migrate to the regional lymph nodes to present viral antigen to naïve T cells, pushing their differentiation and migration into affected tissue . Among tMore than 40% of recovered COVID-19 patients developed pulmonary fibrosis  and pulmIn kidney transplant recipients, then, immunosuppressive agents may have an impact in pulmonary fibrosis . In partNumerous clinical data have reported an incidence of pulmonary complications in mTOR-I-treated kidney transplant recipients of 2–11%, with the onset of symptoms until 5 years after the initiation of sirolimus or everolimus therapy . There aThis pulmonary toxicity seems to be dose-dependent since clinical and radiologic improvement has been observed in a large number of kidney transplant recipients after mTOR-Is dose reduction .The pathogenic mechanism of mTOR-Is induced pulmonary toxicity is unknown but epithelial to mesenchymal transition (EMT) may have an important role . During Additionally, being EMT regulated by several signaling factors such as TGF-β, epidermal growth factor (EGF), fibroblast growth factor (FGF), IL-1, connective tissue growth factor (CTGF), insulin-like growth factor-2 (IGF-2), nuclear factor-kB (NF-kB) and Wnt , pro-fibContrarily, other studies have reported that mTOR-I, whether administrated at low dosage, may exert anti-fibrotic effects . PontrelTherefore, based on these results, we encourage transplant clinicians, whenever possible, to prescribe low dose of everolimus/sirolimus in kidney transplant recipients in order to maximize therapeutic efficacy  and minimize the risk of developing this complication.The PI3K/AKT/mTOR pathway has been shown to be targeted by various viruses, including influenza virus, herpesvirus, hepatitis C virus and adenovirus , and recThis effect has been also observed in rapamycin-treated cells infected with MERS-CoV and 1918 influenza A virus . LikewisIn addition, as reported by Garcia et al., nanomolar concentrations of berzosertib, AZD2014 and Torin-2 may exert important anti-SARS-CoV-2 effects by targeting PI3K/AKT/mTOR pathway .in vitro study performed in a human hepato cellular carcinoma cell line demonstrated that rapamycin and Torin-1 failed to block viral infection , could also decrease antibody class-switch recombination altering the pattern of immunoglobulin (Ig) G and IgM specificities . It has Specific deletion of mTOR in T cells, then, might impair their differentiation in Th1, Th2 or Th17 effector cells (by a direct down-regulation of STAT and other lineage specific transcription factors ) and ind+  versus placebo in hospitalized patients with severe COVID-19. The primary outcome is death or progression to respiratory failure requiring advanced respiratory at day 28.NCT04461340 asseses the efficacy and safety of sirolimus as an adjuvant agent to the standard treatment protocol against COVID-19. It is a single-blinded randomized study in which participants are randomly assigned to sirolimus  plus national standard of care therapy against COVID-19 or only national standard of care therapy against COVID-19.Interestingly, the trial NCT04948203 evaluates the efficacy of sirolimus in preventing post-COVID-19 pulmonary fibrosis. The hospitalized patients with <10% pulmonary fibrosis, evaluated by CT at admission, are divided in three groups according to different dose regimens of sirolimus  for 14 days. Pulmonary fibrosis is, then, evaluated by CT scan after 12 weeks.In COVID-19 kidney transplant recipients, at the moment, we do not have enough evidence to support the hypothesis that mTOR-I may antagonize recovery or promote pulmonary complications and contrasting results have been obtained in observational studies  Table 1Table 1. However, although a withdrawal of immunosuppression may have positive effects by restoring the host immunity, it could expose patients to a high risk of acute rejection with negative clinical and psychological impact.Therefore, mTOR-Is discontinuation should be reserved to kidney transplant recipients with severe COVID-19, while it should be, if possible, avoid in asymptomatic/paucisymptomatic patients in order to do not increase their risk to develop an immune-mediated graft impairment and to take advantage of some potential antiviral proprieties of these agents.Several clinical trials have reported a reduced rate of Cytomegalovirus and BKV infections in kidney transplant recipients treated with mTOR-Is alone or associated to low dosages of calcineurin inhibitors (CNI) compared to those in standard dose CNI regimen . The exavia the STAT3 pathway may reduce the expression of receptors for IL-6 and IL-6 production  has been only partially elucidated. We can only suppose that, being mTOR a central kinase of the cellular metabolism, its inhibition may have consequence on the pharmacological effects of these agents. As reported by Weichhart et al., corticosteroids, inducing the expression of REDD1, may potentiate the pharmacological inhibition of the mTOR pathway. This is in line with previous data obtained in patients affected by H1N1 influenza virus . Additiooduction , that maAll the above mentioned effects need to be analyzed in specific research project involving organ transplant recipients.Solid organ transplant candidates and recipients are identified as a priority population for COVID-19 vaccines, given the higher risks associated with immunosuppressed status. Currently, vaccines employable for transplant recipients are BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna).However, data regarding safety, immunogenicity, and efficacy in these patients are scarce. Some evidence indicates that solid organ transplant recipients who receive mRNA-based vaccines have low immunization rates  and alsoFactors associated with negative humoral response to vaccine were older age, high-dose corticosteroids treatments, maintenance with triple immunosuppressive medications and a regimen that includes anti-metabolite . The eff+ effector memory T cells obtained by mTOR-I  in these patients to potentiate their immunocompetence and minimize the risk of clinical complications of severe COVID-19.However, at our opinion, in kidney transplant recipients in mTOR-Is-based immunosuppressive therapy, this “discontinuation strategy” should be reserved for patients with severe COVID-19. Instead, in asymptomatic patients or those with mild COVID-19 symptoms, a “wait and see approach” or a reduction of the dosage of these agents may be useful to minimize the risk of acute allograft rejection development and to exploit their potential anti-viral and anti-fibrotic effects. The reduction of the dosage may partially restore the host immunity facilitating the disease recovery, antagonize/mitigate the onset of cytokine storm, and preserve Treg growth and activity, which could reduce the progression to severe COVID-19.Moreover, additional clinical studies aimed to evaluate the impact of mTOR-I on the vaccines and to assess the efficacy and safety of the use of mTOR-I alone or in combination with other new anti-fibrotic agents in kidney transplant recipients with COVID-19 are necessary to allow a more efficient treatment of the acute clinical phase and facilitate the recovery from post-acute COVID-19. Indeed, while most people with COVID-19 recover completely within a few weeks, some patients experience lasting symptoms  that can continue for weeks or even months after initial recovery.Finally, we believe that molecular biology (particularly omics techniques) may represent powerful methods that could help kidney transplant clinicians to discover new therapeutic strategies for SARS-CoV-2 infection, to select new biomolecular targets and to personalize its treatments .


Postoperative adjuvant cisplatin-based chemotherapy had been the standard care in patients with completely resected high-risk stage IB to IIIA non-small cell lung cancer (NSCLC) for decades. However, the survival benefits were far from satisfactory in clinical practice. Thus, this meta-analysis was performed to compare the efficacy and safety of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with resected NSCLC based on updated literature and research.A systematic literature search based on random control trials (RCTs) was conducted with keywords on PubMed, Embase and the Cochrane library databases. All articles compared EGFR-TKIs to placebo or chemotherapy as adjuvant therapies for early-stage resected NSCLC. A meta-analysis was performed to generate combined hazard ratio (HR) with 95% confidence intervals (CI) for disease-free survival (DFS), overall survival (OS), and risk ratio (RR) with 95% CI for disease recurrence and adverse events (AEs). The Stata statistical software (version 14.0) was used to synthesis the data.EGFR) mutations , but had no impact on OS . The subgroup analyses indicated that adjuvant EGFR-TKIs were superior in regard to DFS in most subgroups, including varied smoking status, EGFR mutations type, gender, age, Eastern Cooperative Oncology Group performance status and adenocarcinoma. Osimertinib resulted in decreased brain recurrence than first generation of EGFR-TKIs . The AEs were generally manageable and tolerable. The incidence of high-grade (≥ 3) AEs including diarrhea  and rash  increased after adjuvant EGFR-TKIs treatment.A total of 9 RCTs comprising 3098 patients were included. Adjuvant EGFR-TKIs could significantly prolong DFS in patient with resected NSCLC harboring epidermal growth factor receptor (EGFR mutation-positive NSCLC, but had no impact on OS. Adjuvant EGFR-TKIs could be an important treatment option in patients with resected early-stage EGFR-mutant NSCLC.Adjuvant EGFR-TKIs therapy could significantly prolong DFS in patients with completely resected early-stage The online version contains supplementary material available at 10.1186/s12885-022-09444-0. EGFR) mutation status for decades . The updated data showed that subsequent therapies greatly influenced OS and continuing EGFR-TKIs contributed most to OS in ADJUVANT trial. In addition, the duration of EGFR-TKIs might also influenced the prognosis. The average duration of adjuvant EGFR-TKIs was 24 months in most of the clinical trials [Despite improvements in DFS, adjuvant EGFR-TKIs versus chemotherapy or placebo had not substantially improved OS in patients with operable NSCLC, not matter what the tastasis . The finl trials , 20–22. l trials , 29. So,EGFR kinase activity and was structurally different from other generations of TKI [EGFR sensitizing mutations and EGFR second mutation cell lines, which resulted in substitution of threonine at amino acid 790 to methionine (T790M), in vitro [EGFR mutations [EGFR sensitizing mutations and T790M positive NSCLC, subsequently [.Subgroup analysis demonstrated that the risk of brain recurrence was significant reduced when patients treated with adjuvant osimertinib than with first generation of EGFR-TKIs. Why osimertinib could reduce the rate of brain metastasis? First, osimertinib was a potent and irreversible inhibitor of s of TKI . Second,in vitro . In addiutations . On the equently , 40. Theequently .s. First, the final goal of adjuvant treatment was to improve the OS, but DFS rather than OS was designed as the primary endpoint in most clinical trials. Although DFS could be applied as a surrogate of OS for NSCLC, this pattern was mainly existed in studies treated with chemotherapies in which DFS was consistent with OS [However, there still remains a few problems in the treatment of adjuvant EGFR-TKI with OS . However with OS . Third, EGFR mutations was too low in BR 19 trial which may influenced the result greatly . Second, both first and third-generation EGFR-TKIs were included in this meta-analysis. The reasons were as follows: (1) both of them belonged to small molecule EGFR-TKIs, aiming at blocking the EGFR signal pathway and inhibiting tumor growth; (2) they were all recommended in the first-line treatment of advanced NSCLC harboring EGFR mutations; (3) few published articles focused on the effect of third-generation TKIs as adjuvant treatment and the excellent outcome generated from ADAURA trial made us produce the data synthesis in one single analysis. Third, the follow-up was short in most of the included studies. The IMPACT had a median follow-up of 70 months and the result showed adjuvant gefitinib seemed to prevent early relapse than adjuvant cisplatin plus vinorelbine, but the two curves with respect to DFS crossed about 4 years after surgery. Therefore, longer follow-up might represent different outcomes. Forth, most clinical trials excluded patients with uncommon EGFR mutations, which harbored heterogeneous molecular alterations within exons 18–21 and collectively accounted for 10% of EGFR mutations. Previous studies showed that the clinical efficacy of EGFR-TKIs in advanced NSCLC harboring EGFR uncommon mutations was variable and the OS was shorter when compared to classical mutations [EGFR mutations.Besides, there were some limitations in our analysis. First, the definition of experimental and control groups had a shortcoming that the control group included adjuvant placebo or adjuvant chemotherapy without specific distinguishing. In order to reduce the bias, additional analyses were conducted according to different interventions of experimental and control groups  DFS for the intent-to-treat patients with regardless of the EGFR mutations status. (B) DFS for patients harboring EGFR mutations.Additional file 2 Supplementary Fig. 2. Comparison of DFS and OS among adjuvant EGFR-TKIs versus chemotherapy subgroup, adjuvant EGFR-TKIs versus placebo, adjuvant chemotherapy plus EGFR-TKIs versus adjuvant chemotherapy subgroup. (A) DFS comparison. (B) OS comparison.Additional file 3 Supplementary Fig. 3. Comparison of local recurrence, distant metastasis and other subgroup recurrences between adjuvant EGFR-TKIs versus adjuvant chemotherapy/placebo. (A) Local recurrence. (B) Distant metastasis. (C) The subgroup recurrences


Innovative nucleoside-modified viral messenger RNA (v-mRNA)—based vaccines encapsulated within nanoparticles—specifically lipid ones (LNPs)—are now well recognized. Although this is a promising genetic engineering topic in the field of nanopharmacogenomics or targeted nucleic vaccines, there are limited but continuously enriched in vivo data in depth of time regarding their safety, efficacy, and immune response. In the current paper we expand the limited published data in the field of ribosome machinery and SARS-CoV-2 mRNA fragment vaccines interaction by describing their functional specialization and modifications. Additionally, alterations in post-transcriptional/translational molecules and mechanisms that could potentially affect the interaction between target cells and vaccines are also presented. Understanding these mechanisms is a crucial step for the next generation v-mRNA vaccines development.Coronavirus-related Severe Acute Respiratory Syndrome-2 (SARS-CoV-2) initially was detected in Wuhan, Hubei, China. Since early 2021, World Health Organization (WHO) has declared Coronavirus Disease 2019 (COVID-19) a pandemic due to rapidly transformed to a globally massive catastrophic viral infection. In order to confront this emergency situation, many pharmaceutical companies focused on the design and development of efficient vaccines that are considered necessary for providing a level of normalization in totally affected human social-economical activity worldwide. A variety of vaccine types are under development, validation or even some of them have already completed these stages, initially approved as conditional marketing authorisation by Food and Drug Administration (FDA), European Medicines Agency (EMA), and other national health authorities for commercial purposes ( Furthermore, massive production of safe and effective vaccines initially validated by multi-omics—based integrated analyses is another critical aspect  in 2002/2003, Middle-East Respiratory Syndrome (MERS-CoV) in 2012/2013, and especially the current 2019/2020 Severe Acute Respiratory Syndrome-2 (SARS-CoV-2) led to an unpredictable stress regarding the national health systems’ endurance worldwide . Rapidlyl aspect . Efficieelerated . Nucleoselerated . In the elerated .Structural biology evolution has revealed human ribosome (HR) biogenesis as a major and most significant event for the cellular micro-environmental homeostasis. Mature HRs are macromolecular complexes that act as intracellular network factories  providing a continuous protein synthesis . They arBased on extensive molecular/structural analyses of the cellular micro-environment, there is strong evidence that ribosome heterogeneity exits and affects crucially the post-transcriptional and translational procedures . ContinuBesides ribosome specialization, ribosome dysfunction -caused by genetic alterations—negatively affects normal cell translational machinery. Abnormal ribosome biogenesis mediated by specific point mutations is implicated in the onset of congenital human disorders (syndromes) including X-linked dyskeratosis congenita, Treater Collins syndrome, Diamond—Blackfan anemia, 5q-syndrome, Schwachman—Diamond syndrome, and also Cartilage hair hypoplasia . AccordiSARS-Cov-2 virus belongs to lineage b of beta-CoVs demonstrating a strong phylogenetic similarity with BatCoVRaTG13 type . The virin vivo use in general population, accelerating their production and distribution process  or stabilized S protein (m RNA-1273) . Concernin vivo and broken down in the intracellular microenvironment. In fact, cells have developed specific RNA- mRNA energy depended mechanisms for mediating mRNA transport from the transcription to translation sites or in the case of extracellular ones to the ribosome machinery only  conditions are obligatory by now in order LNP-mRNA complex to be secured and drastically effective inside the intracellular environment. Concerning the risk in interacting with the nuclear microenvironment (host DNA), it seems to be very low. In contrast, a recently published study reported the possibility for RNA viruses—including SARS-CoV-2—to interfere with the crucial p53 “guardian of the genome” nuclear phospoprotein function . The preET, AC, VP, and EK wrote the manuscript. NM, VR, AB, DP, NK, and AL were academic advisors. ET produced the figure (scheme). All authors contributed to the article and approved the submitted version.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.


Lichen planus pigmentosus-inversus (LPP-inversus) is a rare, pigmented variant of lichen planus of unknown etiology. This skin condition typically affects the intertriginous and flexural regions of the body bilaterally. We report an unusual case presentation with unilateral distribution of LPP-inversus in a woman originally from Nepal. The lesions developed rapidly over a three-month period and were recalcitrant to therapy with topical clobetasol and hydroquinone. Lichen planus pigmentosus (LPP) is a rare, pigmented variant of lichen planus, characterized by symmetric, gray to dark brown macules or patches primarily affecting sun-exposed areas such as the face and neck. LPP-inversus is a term used for LPP lesions located on sun-hidden areas such as intertriginous and flexural regions . Pock etA 32-year-old Nepalese woman with a history of hypercholesterolemia presented with a dark-brown, pruritic rash on her right upper thigh and groin. The rash had rapidly developed over three months without any known triggers. The patient denied any new exposures or medications and had no known allergies. Physical examination revealed multiple well-demarcated, hyperpigmented macules and patches on the right proximal thigh and inguinal fold. The lesions had a “splatter-like” arrangement along Blaschko lines Figure . Nail, sLPP-inversus is less common and clinically distinct from classic LPP as it predominantly occurs in non-sun-exposed, intertriginous, and flexural areas such as the axilla and groin . In 2001As LPP-inversus is a relatively rare disease, the exact prevalence is still unknown. Based upon limited data, this skin condition has variable epidemiology with an age of presentation ranging from 5 to 84 years ,7. PediaThe etiology of LPP-inversus is not completely understood. The proposed pathophysiology involves direct T lymphocyte-mediated cytotoxic destruction of basal keratinocytes leading to inflammatory changes and pigment incontinence ,10. ChroClinical differential diagnosis includes erythrasma, acanthosis nigricans, ashy dermatosis, post-inflammatory hyperpigmentation, and fixed drug eruption. A biopsy is helpful in confirming the diagnosis of LPP-inversus. Histopathologically, LPP-inversus appears similar to lichen planus with band-like lymphohistiocytic infiltrate in the papillary dermis with interface vacuolar changes; however, LPP-inversus may show a regressive pattern with epidermal atrophy and minimal-to-absent hyperkeratosis and hypergranulosis. In addition, pigment incontinence is prominent .LPP-inversus has a benign but recalcitrant clinical course; occasionally, lesions resolve spontaneously. There are currently no standardized guidelines for the management of this condition. Treatments such as topical corticosteroids, oral corticosteroids, and topical tacrolimus have produced inconsistent results . Dimova We describe a case of unilateral presentation of LPP-inversus resistant to topical clobetasol and hydroquinone in a Nepalese woman. Our results suggest that these two treatments may not be effective for every patient with this skin condition. Additional studies on the etiology and pathophysiology of LPP-inversus may lead to more targeted treatments and improved patient outcomes.


COVID-19, the infectious disease caused by SARS-CoV-2, has claimed the lives of over 4.5 million people worldwide as of 18 September 2021 , which h68Ga-PSMA-11-PET/CT for prostate cancer [68Ga-PSMA-11 uptake in the lungs, but only a single patient actually had lung metastasis. This finding highlights the potential confounding effect of COVID-19 on prostate cancer staging using nuclear medicine techniques.In the particular case of prostate cancer, the second most frequently diagnosed cancer in men, the COVID-19 pandemic has had a negative impact both on early diagnosis by reducing participation to screening programs  and on te cancer , all of Overall, the findings discussed here show how COVID-19 has deeply affected all aspects of prostate cancer care, including early diagnosis, treatment and staging, with negative consequences that are not fully predictable and understandable at the present time. On the other hand, it is foreseen that SARS-CoV-2 will continue to circulate despite mass vaccination programs, so a continued effort to analyze its effects on prostate cancer care is mandatory. Physicians treating prostate cancer should consider preferring oral compared with intravenous agents and performing remote visits, if feasible. Also, they should be aware that COVID-19 may affect accuracy of some imaging techniques such as PSMA (prostate specific membrane antigen) PET. On the other hand, research should focus on the potential interaction of COVID-19 with available treatments against prostate cancer, which remains largely ignored. As an example, patients with localized prostate cancer recovering from COVID-19 may represent a clinically significant population requiring a specific treatment algorithm regarding the use of surgery versus radiotherapy. Also, patients with metastatic prostate cancer with a history of symptomatic COVID-19 might suffer from more severe adverse events associated with chemotherapy. Observational prospective and retrospective studies designed to assess the impact of COVID-19 on treatment efficacy and toxicity remain a compelling need regardless of the success of vaccination campaigns in SARS-CoV-2 eradication in the complex scenario caused by this vicious and unprecedented pandemic.


Atherosclerosis is an inflammatory disease in which lipids accumulate on the walls of blood vessels, thickening and clogging these vessels. It is well known that cell-to-cell communication is involved in the pathogenesis of atherosclerosis. Exosomes are extracellular vesicles that deliver various substances  from the donor cell to the recipient cell and that play an important role in intercellular communication. Atherosclerosis can be either induced or inhibited through cell-to-cell communication using exosomes. An understanding of the function of exosomes as therapeutic tools and in the pathogenesis of atherosclerosis is necessary to develop new atherosclerosis therapies. In this review, we summarize the studies on the regulation of atherosclerosis through exosomes derived from multiple cells as well as research on exosome-based atherosclerosis treatment. Atherosclerosis is an inflammatory vascular disease caused by lipid accumulation in the vessel wall, which leads to plaque formation, narrowing the vessel lumen ,2. The iExosomes play an important role in cell-to-cell communication ,12. ExosDue to their biocompatibility and ability as carriers, exosomes can be used as a molecular therapeutic agent ,26. To uThere are some ongoing clinical trials on the use of exosomes for the treatment of diverse diseases ,29,30. FThe atherosclerosis condition progresses through the communication between diverse cells using exosomes. Exosomes affect the function of VSMCs, ECs, and macrophages to regulate atherosclerosis. Understanding these exosomes and the variety of their cargo substances provides information on the progression and treatment of atherosclerosis. Several studies on this topic focus on analyzing exosomes derived from atherogenic cells induced by oxidized-low density lipoprotein (ox-LDL), diabetes inducer, or nicotine or those from atherogenic patient plasma ,38,39,40Foam cell formation from macrophages induced by ox-LDL plays an important role in the early procession of atherosclerosis . Foam ceOx-LDL-treated THP-1 monocyte-derived exosomes induced atherosclerosis. Hu et al., observed that the expression of the long non-coding RNA (lncRNA) LIPCAR was increased in exosomes derived from ox-LDL-treated THP-1 cells . LIPCAR Martinus et al., found that exosomes derived from THP-1 cells under diabetic conditions with 25 nM glucose had high expression of HSP60, a mitochondrial molecular stress protein . HSP60 iZhu et al., investigated exosomes derived from nicotine-treated macrophages as nicotine is known to induce the development of atherosclerosis ,38,39,40Exosomes derived from ox-LDL-treated VSMCs promote atherosclerosis by reducing EC barrier function. According to previous studies, Krüppel-like factor 5 (KLF5) induces atherosclerosis by promoting VSMC proliferation and migration ,51. ZhenExosomes derived from human aortic smooth muscle cells (HAoSMCs) inhibit autophagy in HUVECs. Li et al., found that miR-221/222 is enriched in HAoSMC-derived exosomes and targets PTEN, subsequently activating the Akt pathway . TherefoExosomes released from ECs regulate VSMC phenotype changes, which play an important role in atherosclerosis ,55,56. LExosomes derived from ox-LDL-treated HUVECs induce pro-inflammatory M1 polarization in THP-1 monocytes, a typical feature of atherosclerosis. Interestingly, miR-155 is highly expressed in ox-LDL-treated HUVEC-derived exosomes as well as in ox-LDL-treated VSMC-derived exosomes . In ox-LExosomes derived from mature DCs affect endothelial inflammation and atherosclerosis through the membrane tumor necrosis factor-α (TNF-α)-mediated nuclear factor (NF)-κB signaling pathway . Zhong eWhile exosomes derived from various cells can promote atherosclerosis, exosomes derived from MSCs, endothelial progenitor cells (EPCs), bone marrow-derived macrophages (BMDMs), and platelets have been found to ameliorate atherosclerosis. In particular, exosomal miRNAs play a role in the inhibition of atherosclerosis . StudiesMSC-derived exosomes have been proven to have therapeutic effects in atherosclerosis . When oxMouse bone marrow MSC-derived exosomes prevent atherosclerosis by promoting EC proliferation due to reduced apoptosis and expression of inflammatory cytokines. miR-512-3p is enriched in MSC-derived exosomes and targets Keap1, an Nrf2 inhibitor . Nrf2 isApoE(−/−)) mice fed a high-fat diet. ApoE(−/−) mice fed a high-fat diet showed poor lipoprotein clearance, which promotes the development of atherosclerotic plaques due to accumulation of cholesterol ester-rich particles in the blood [In addition, MSC-derived exosomes reduced the area of atherosclerotic plaque and the infiltration of macrophages in the plaque, and promoted M2 macrophage polarization in apolipoprotein E-deficient  mice fed a high-fat diet [Chil3 and Retnla compared to normal BMDM-derived exosomes [BMDM-derived exosomes reduced inflammation and hematopoiesis while inducing macrophage polarization in fat diet . BMDM-defat diet ,78. Thesexosomes .ApoE(−/−) mice fed a high-fat diet [When platelets are activated, they adhere to the linear vessels and inhibit atherosclerosis ,80. Throfat diet . The miRExosomes are being used as therapeutic tools for atherosclerosis treatment through exploitation of their role as carriers to deliver therapeutic substances such as miRNAs, mRNA vectors, or molecules that have therapeutic ability. Some exosomes carrying specific substances have documented therapeutic effects in mouse models of atherosclerosis .ApoE(−/−) mice fed a high-fat diet, miR-125b-5p levels were lower, while its target Map4k4 levels were higher than in normal mice [MCP-1 mRNA and serum levels of TNF-α and IL-6 in ApoE(−/−) mice fed a high-fat diet, which suppressed inflammation. The blood lipid levels and plaque formation in ApoE(−/−) mice fed a high-fat diet were also reduced through miR-125b-5p-mediated downregulation of Map4k4, a positive regulator of the NF-κB signaling pathway.In mal mice . Accordimal mice . Lin et mal mice . The injLDLR) can cause familial hypercholesterolemia (FH) [Ldlr mRNA-enriched exosomes on LDLR deletion (Ldlr(−/−)) mice as an FH model [Ldlr(−/−) mice fed a high-fat diet were injected with Ldlr mRNA-enriched exosomes isolated from alpha mouse liver cells (AML12) transfected with Ldlr-expressing vector. Injection of Ldlr mRNA-enriched exosomes resulted in therapeutic effects including reduced liver steatosis, inflammation, LDL levels, and atherosclerotic lesions in FH mouse models.Hypercholesterolemia is a causative agent of atherosclerosis . Inheritmia (FH) . Li et aFH model . Ldlr(−/ApoE(−/−) mice fed a high-fat diet [KLF2, whose expression is induced by shear stress, changes the endothelial cell phenotype to an atheroprotective phenotype . Hergenrfat diet . As a refat diet ,89,90; tApoE(−/−) mice fed a high-fat diet. When free HAL and HAL@M2 exosomes were intravenously injected into mice and their locations were tracked, most HAL@M2 exosomes were located and accumulated in the inflamed abdominal cavity, while free HAL was located mostly in the liver, indicating inflammation tropism of HAL@M2 exosomes. These results raise expectations for a more selective anti-inflammatory effect for the treatment of atherosclerosis through exosomes.The FDA-approved hexyl 5-aminolevulinate hydrochloride (HAL) is known to have anti-inflammatory effects by initiating the biosynthesis of anti-inflammatory bilirubin ,92,93. WIntercellular communication is an important process in the development of atherosclerosis. The pathogenesis of atherosclerosis does not simply progress in one direction of each cell, but instead progresses through the communication of several cell types. Substance exchange through exosomes among different cell types including ECs, VSMCs, and macrophages is known to regulate atherosclerosis progression. Phenotypes associated with atherosclerosis change according to the cells of origin of exosomes and/or recipient cells. In this review, we summarize the diverse cell-to-cell communications using exosomes that are associated with atherosclerosis. Exosomes transfer diverse proteins, miRNAs, and lncRNAs as atherosclerotic inducers or inhibitors. In addition, we provide an overview of studies showing the potential of using exosomes as a therapeutic tool for atherosclerosis.ApoE(−/−) mice fed a high-fat diet. MSCs, EPCs, BMDMs, and platelet-derived exosomes show therapeutic potential for atherosclerosis treatment as they transfer miRNAs. Modified exosomes carrying therapeutic agents such as miRNAs, mRNAs, or drugs also showed therapeutic effects on atherosclerosis. We noticed that enriched exosomal miRNAs identified to have therapeutic effects on atherosclerosis differ depending on the origin of the donor cell. Further investigation of miRNAs commonly enriched in exosomes that have therapeutic effects on atherosclerosis may help in the development of new therapeutic strategies using exosomes.Several early studies report the use of exosomes for the diagnosis of specific diseases ,96. IndeIn atherosclerotic conditions, the expression of KLF2 and KLF5 is regulated in vascular cells, which affects the expression of certain miRNAs in exosomes derived from these cells ,87. ReduAlthough the use of exosomes as therapeutic agents has great potential because exosomes can deliver therapeutic substances as carriers and have biocompatibility, there are still several limitations related to their temporal production and quantitative efficiency . To over


Micro-ribonucleic acids (microRNAs) are small molecules that take part in the regulation of gene expression. Their function has been extensively investigated in cardiovascular diseases (CVD). Most recently, miRNA expression levels have been suggested as potential biomarkers of platelet reactivity or response to antiplatelet therapy and tools for risk stratification for recurrence of ischemic evens. Among these, miR-126 and miR-223 have been found to be of particular interest. Despite numerous studies aimed at understanding the prognostic value of miRNA levels, no final conclusions have been drawn thus far regarding their utility in clinical practice. The aim of this review is to critically appraise the evidence on the association between miRNA expression, cardiovascular risk and on-treatment platelet reactivity as well as provide insights on future developments in the field. Cardiovascular diseases (CVD) remain the most common cause of death worldwide, accounting for 4.1 million deaths per year among European Society of Cardiology (ESC) member countries .The diagnosis of acute coronary syndrome (ACS), comprising ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI) and unstable angina (UA) , require12 receptor antagonists—such as clopidogrel, prasugrel or ticagrelor—represents the cornerstone of ACS management. Nevertheless, some ACS patients exhibit impaired or exaggerated response to antiplatelet agents. The presence of high platelet reactivity (HPR), as assessed by platelet function testing, is associated with an increased risk of recurrent ischemic events in the setting of patients undergoing percutaneous coronary intervention (PCI) [DAPT consisting of the combination of aspirin and a P2Yon (PCI) . On the on (PCI) ,7,8. Genon (PCI) ,9,10; hoon (PCI) . Since ion (PCI) . To thison (PCI) ,15. The Caenorhabditis elegans [MicroRNA is a small non-coding RNA consisting of approximately 22 nucleotides, first discovered in 1993 in nematode species  elegans . At pres elegans . MicroRN elegans . Pri-miR elegans . The cyt elegans . The fol elegans   have reduced levels of circulating miR-126, miR-17, miR-92a, miR-155 and miR-145 in comparison to healthy volunteers, whereas miR-133a and miR-208a levels have shown to be elevated . Platele+ progenitor cells isolated from patients with STEMI compared to stable CAD patients and healthy controls. Moreover, miR-378 was found to be a crucial regulator of the proangiogenic activity of CD34+ progenitor cells [MiR-378 and let-7b were significantly upregulated in mobilized CD34or cells . A lot oor cells .12 inhibitor, constitutes an essential treatment in patients with CAD [12 inhibitor. However, some patients present with inadequate response to clopidogrel, which might be associated with an increased risk of cardiovascular events. It is estimated that about 4% to 30% of patients do not respond to DAPT adequately [12 inhibitors such as prasugrel or ticagrelor are advocated, however, at the expense of the higher bleeding risk [12 inhibitor de-escalation in the late phase after myocardial infarction) [Aspirin, in combination with a P2Ywith CAD . Clopidoequately . More poing risk . Hence, arction) .For these reasons, novel biomarkers evaluating the probability of inadequate response to antiplatelet therapy are continuously required. In this context, the potential utility of platelet miRNA for identification of patients with anticipated high on-treatment platelet reactivity is gaining an increased interest. Aspirin treatment in diabetes mellitus type 2 (DM2) patients resulted in a decreased level of circulating miR-126, most likely due to an inhibitory effect on platelet activation and miRNA-containing microvesicle release . Healthy12 inhibitors) can be assessed by measuring platelet reactivity while on treatment. High on-treatment platelet reactivity is identified when platelet reactivity remains elevated despite applied therapy [Resistance to clopidogrel  in each study . It brin12 mRNA and thereby regulating this ADP receptor expression [12 assay. When taking a vasodilator-stimulated phosphoprotein (VASP) assay into consideration, correlation was observed not only in case of miR-126, but also in miR-223 and miR-24 [12 receptors (like miR-223), but it also downregulates the expression of ADAM9 in megakaryocytes, a gene encoding protease potentially involved in platelet–collagen interactions [Zhang et al. determined that the circulating miR-223 level was decreased in low-responders to clopidogrel as compared to normal-responders among non-ST-elevation acute coronary syndrome (NTSE-ACS) patients. Moreover, correlation between miR-223 level and platelet reactivity index (PRI) was found . Althougpression . Kaudewid miR-24 . MiR-126d miR-24 . Not onlractions . Kok et ractions .12 inhibitor therapy in CAD patients, plasma levels of miR-21, miR-126, miR-150 and miR-223 remained unaltered; however, the expression of these miRNAs was affected by the P2Y12 inhibitor choice, being increased in patients taking ticagrelor as compared to clopidogrel and prasugrel [Conversely, Li et al. demonstrated that despite platelet miR-21 and miR-126 expression being decreased, as well as miR-150 and miR-223 expression being increased in STEMI patients, compared to healthy individuals, there was no correlation between intraplatelet miRNAs and platelet reactivity—as expressed both by platelet reactivity unit (PRU) and VASP . Using brasugrel . Tang etrasugrel .Becker et al. investigated two independent cohorts of NSTE-ACS patients finding that circulating levels of miR-15b-5p, miR-93 and miR-126 were consistently correlated with platelet reactivity . Zhang eDifferent methodologies of sample extraction, microRNA detection and analysis need to be considered while interpreting results of the discussed studies. Firstly, some investigations assessed circulating miRNA whilst the other intraplatelet miRNA. Secondly, platelet reactivity was measured with varied tests, of which the VerifyNow and VASP methods were the most commonly applied. Furthermore, analyses were performed at different timepoints regarding DAPT treatment initiation and administration.The majority of studies carried out to date enrolled rather small patient groups and judicious interpretation of each finding is indicated. Still, the current evidence could identify meaningful associations which may be useful in guiding target biomarkers’ selection in future larger studies. In particular, the development of microRNA panels, rather than single particle analysis, and identification of high-risk microRNA profiles or ‘fingerprints’ indicative of cardiovascular, as well as impaired pharmacotherapy response hazards appear the most promising targets for future investigations. Nevertheless, standardisation of currently employed analytical methods is warranted before any wider clinical adoption of microRNA as diagnostic tool. The studies addressing the role of microRNA as indices of novel antiplatelet agents’ efficacy should employ the same miRNA for qPCR normalisation, and more rigorous protocols of blood sampling in order to both increase the accuracy of analytical methods and to minimise the impact of time between drug administration and sample collection on measured miRNA levels which could affect the results. Baseline microRNA evaluation before DAPT initiation as well as appropriate longitudinal modelling of serial measurements is strongly recommended . All newReliable monitoring of the response to antiplatelet aggregation therapy remains a major challenge. The methods of platelet function assessment developed to date include light transmission platelet aggregometry (LTA), multiple electrode aggregometry, Vasodilator Stimulated Phosphoprotein (VASP) phosphorylation by flow cytometry or VerifyNow system ; howeverDespite marked advances in CVD management, there remains a clear need for improved and earlier identification of at-risk subjects to prevent cardiovascular events and safely escalate pharmacotherapy in resistant individuals. Recent evidence suggests correlations between several miRNAs expression and on-treatment platelet reactivity, although there is some heterogeneity between reports, which warrants further studies in the field. There is a need for truly longitudinal biomarker studies with serial blood sampling, paying particular attention to valid methodology of sample preparation, microRNA detection as well as statistical elaboration of the results.


Obesity decreases the secretion of SARS-CoV-2-specific IgG antibodies in the blood of COVID-19 patients. How obesity impacts the quality of the antibodies secreted, however, is not understood. Therefore, the objective of this study is to evaluate the presence of neutralizing versus autoimmune antibodies in COVID-19 patients with obesity.Thirty serum samples from individuals who tested positive for SARS-CoV-2 infection by RT-PCR were collected from inpatient and outpatient settings. Of these, 15 were lean (BMI < 25) and 15 were obese (BMI ≥ 30). Control serum samples were from 30 uninfected individuals, age-, gender-, and BMI-matched, recruited before the current pandemic. Neutralizing and autoimmune antibodies were measured by ELISA. IgG autoimmune antibodies were specific for malondialdehyde (MDA), a marker of oxidative stress and lipid peroxidation, and for adipocyte-derived protein antigens (AD), markers of virus-induced cell death in the obese adipose tissue.SARS-CoV-2 infection induces neutralizing antibodies in all lean but only in few obese COVID-19 patients. SARS-CoV-2 infection also induces anti-MDA and anti-AD autoimmune antibodies more in lean than in obese patients as compared to uninfected controls. Serum levels of these autoimmune antibodies, however, are always higher in obese versus lean COVID-19 patients. Moreover, because the autoimmune antibodies found in serum samples of COVID-19 patients have been correlated with serum levels of C-reactive protein (CRP), a general marker of inflammation, we also evaluated the association of anti-MDA and anti-AD antibodies with serum CRP and found a positive association between CRP and autoimmune antibodies.Our results highlight the importance of evaluating the quality of the antibody response in COVID-19 patients with obesity, particularly the presence of autoimmune antibodies, and identify biomarkers of self-tolerance breakdown. This is crucial to protect this vulnerable population at higher risk of responding poorly to infection with SARS-CoV-2 than lean controls. The novel single-stranded RNA coronavirus SARS-CoV-2 (severe acute respiratory syndrome corona virus-2) emerged in the last months of 2019, caused the worldwide coronavirus disease 2019 (COVID-19) pandemic, and was responsible for different clinical manifestations ranging from mild disease to severe respiratory tract infections, multiorgan failure, and death. The severe manifestations of the disease are associated with an exuberant inflammatory response and the development of a condition known as cytokine storm . In addiResolution of SARS-CoV-2 infection requires both innate and adaptive immune responses that lead to the clearance and elimination of the virus from the organism. B cells contribute to this process by producing neutralizing antibodies that prevent the spread of infectious virions, control virus dissemination, and reduce tissue damage. Neutralizing antibodies generated against the Spike glycoprotein of the SARS-CoV-1 in the 2002–2003 pandemic have shown efficacy in protecting from severe disease . MoreoveObesity is an inflammatory condition associated with inflammaging and chronic IA, contributing to functional impairment of immune cells, and decreased immunity. Obese individuals have been shown to respond poorly to infections –11, vaccWe have previously evaluated the effects of obesity on the secretion of SARS-CoV-2-specific immunoglobulin G (IgG) antibodies in the blood of lean and overweight/obese COVID-19 patients, and we have shown that SARS-CoV-2 IgG antibodies are negatively associated with BMI in COVID-19 patients, as expected based on the known effects of overweight/obesity on humoral immunity . We measExperiments were performed using serum samples isolated from individuals who tested positive for SARS-CoV-2 RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) of nasopharyngeal swab samples. Only serum samples were collected from patients, and samples used in this study were discarded clinical samples, only taken for routine clinical care purposes. Samples were de-identified before being used in this study. In total, 30 serum samples from individuals tested positive for SARS-CoV-2 infection by RT-PCR, 15 lean (BMI < 25) and 15 obese (BMI ≥ 30), were collected from both inpatient and outpatient settings and frozen until testing was performed. Both lean and obese patients had multiple respiratory symptoms , as evaluated at the time of hospital admission, but none was admitted to Intensive Care Unit. The research was approved and reviewed by the Institutional Review Board  at the University of Miami, which reviews all human research conducted under the auspices of the University of Miami.Control serum samples were from 30 uninfected individuals, age-, gender-, and BMI-matched, recruited at the University of Miami before the current pandemic . Both lean and obese uninfected controls were screened for diseases known to alter the immune response or for consumption of medications that could alter the immune response. We excluded subjects with autoimmune diseases, congestive heart failure, cardiovascular disease, chronic renal failure, malignancies, renal or hepatic diseases, infectious disease, trauma or surgery, pregnancy, or documented current substance and/or alcohol abuse.The characteristics of COVID-19 patients and controls are in Table SARS-CoV-2 RNA was detected by RT-PCR of nasopharyngeal swab samples. RT-PCR tests were performed at the clinical laboratories of the Department of Pathology & Laboratory Medicine using either the Diasorin or the BDMax assay and reagents. Depending on submission type (symptomatic or asymptomatic), the sample was assigned and tested per the manufacturer guidelines.Serum IgG antibodies against SARS-CoV-2 Spike protein were measured by an ELISA developed and standardized in our laboratory . BrieflyNeutralizing antibodies were measured by the cPass neutralization ELISA assay, a surrogate plaque reducing neutralization test using the DYNEX Agility® Automated ELISA system. The kit relies on the disruption of the protein–protein interaction between receptor-binding domain-horseradish peroxidase (RBD-HRP) and human angiotensin-converting enzyme 2 (hACE2) by neutralizing antibodies against SARS-CoV-2. First, the samples are preincubated with the RBD-HRP to allow interaction and binding of the antibodies. The sample is then added to the precoated hACE2 protein-coated plate. The plate is then washed, and then TMB is added, producing the blue color. The stop solution is then added, and the wells read at 450 nm. A calibration curve is generated using the cPass standard using the established concentration, and sample results are calculated from the interpolated standard curve.To measure MDA-specific IgG antibodies, ELISA plates were coated with MDA-modified BSA protein , at the concentration of 10 µg/mL. Control ELISA plates were coated with BSA at a concentration of 10 µg/mL. MDA-specific optical density (OD) values were calculated by subtracting BSA OD values from MDA-BSA OD values , 24.To measure AD-specific IgG antibodies, we isolated the adipocytes from the subcutaneous AT of patients undergoing weight reduction surgeries , as previously described . After iFor all tests, serum samples were diluted 1:1000 with sample buffer.Serum levels of CRP were measured using the commercially available kit R&D # DCRP00.p < 0.05 set as a criterion for significance. F and p values generated after mixed-effects analyses were calculated and are reported in each figure legend. We used Student’s t tests (two-tailed) to examine differences between two groups. We used bivariate Pearson’s correlation analyses to examine relationships between variables. GraphPad Prism version 8.4.3 software was used to construct all graphs.We used one-way analysis of variance to examine differences between the four groups of participants . Group-wise differences were analyzed afterward with Bonferroni’s multiple-comparisons test, with The results for Spike-specific IgG antibodies in serum samples of 30 COVID-19 patients and 30 uninfected controls, age-, gender-, and BMI-matched, are shown in Fig. Results in Fig. We evaluated the presence of IgG antibodies with two autoimmune specificities in serum samples of lean and obese COVID-19 patients as compared to uninfected controls. Results in Fig. We measured the association of anti-MDA and anti-AD with serum CRP, a marker of inflammaging previously found to be positively associated with autoimmune antibodies . ResultsThe results from this study show that the majority of COVID-19 patients with obesity make almost undiscernible amounts of neutralizing anti-SARS-CoV-2 antibodies, suggesting that obese individuals may be at a higher risk to respond poorly to SARS-CoV-2 infection. Our results are in disagreement with another study in which obesity was associated with increased fever and multiple severe symptoms of disease caused by SARS-CoV-2 infection but not with dysfunctional B and T cell immune responses . These dThe onset of autoimmunity has been associated with viral infections, and it has been suggested that SARS-CoV-2 could be a triggering factor for the development of a rapid autoimmune, autoinflammatory disease in genetically predisposed individuals as those with high systemic interleukin-6 , 29, simIn the current pandemic, it has been shown that serum samples of adult COVID-19 patients contain antibodies that target the tissues of infected patients instead of targeting the disease-causing virus. Anti-phospholipid, anti-type-I interferons, anti-nuclear antibodies, and rheumatoid factor have been found in a large number of COVID-19 patients and linked to severe disease as they may inactivate critical components of the antiviral response . These fEarly reports have shown that autoimmune IgG antibodies in adult COVID-19 patients are correlated with serum levels of CRP . CRP is We also measured serum Spike-specific IgG antibodies in our cohorts of lean and obese COVID-19 patients and uninfected controls. These antibodies were found to be significantly lower in obese as compared to lean COVID-19 patients, confirming our previously published findings that BMI is negatively associated with anti-Spike IgG serum levels  and metaIn conclusion, our results highlight the importance of identifying protective  versus pathogenic (autoimmune) antibodies in COVID-19 patients with obesity. In addition, similar autoimmune antibodies may also be secreted following COVID-19 vaccination. However, the reactogenicity of lipid nanoparticle-formulated COVID-19 mRNA vaccines in individuals with obesity, characterized by dysregulation of immune responses, has not been investigated yet. Therefore, evaluating the quality of the antibody response of obese COVID-19 patients is crucial to protect this vulnerable population at higher risk of responding poorly to infection with SARS-CoV-2 and vaccination against SARS-CoV-2 lean controls. Although our study has the limitation of having a small number of recruited participants, we believe our results have a high impact showing that obese individuals may be at a higher risk to respond poorly to SARS-CoV-2 infection.


Bilateral Filtering (BF) is an effective edge-preserving smoothing technique in image processing. However, an inherent problem of BF for image denoising is that it is challenging to differentiate image noise and details with the range kernel, thus often preserving both noise and edges in denoising. This letter proposes a novel Dual-Histogram BF (DHBF) method that exploits an edge-preserving noise-reduced guidance image to compute the range kernel, removing isolated noisy pixels for better denoising results. Furthermore, we approximate the spatial kernel using mean filtering based on column histogram construction to achieve constant-time filtering regardless of the kernel radius’ size and achieve better smoothing. Experimental results on multiple benchmark datasets for denoising show that the proposed DHBF outperforms other state-of-the-art BF methods. Edge preservation and smoothing of the content in an image is a basic problem in machine vision, computer graphics, and image processing. To remove shadows from a single input image, Yang et al. recovered a 3-D intrinsic image using edge-aware smoothing from the 2-D intrinsic image . Stereo of image . The worf then describes the above filtering process below:q centred at pixel p in the filter kernel K, and n is a normalization factor, and Gaussian low-pass filtering is a technique that reduces pixels’ differences by weighted averaging for image smoothing in various applications. However, such low-pass filtering cannot preserve image details, e.g., edges and textures. The linear translation-variant function ing (BF)  describess below:f(p)=∑qKpng (BF) [Kp,q(Q)=1ng (BF) [Kp,q(Q)=1In this paper, we extend the existing BF frameworks by proposing a novel Dual-Histogram BF (DHBF) method for better denoising results. The main contributions of ours are threefold.We improve the range kernel in BF based on an edge-preserving noise-reduced guidance image, where isolated noisy pixels are removed to avoid erroneously judging those noisy pixels as edges;We adopt mean filtering based on column histogram construction to approximate the spatial kernel, achieving constant-time filtering regardless of the kernel radius’ size and better smoothing;We conducted an extensive experiment on multiple benchmark datasets for denoising and demonstrated that the proposed DHBF performs favorably against other state-of-the-art BF methods.The remainder of this paper is organized in the following sections. Based on geometric similarity and photometric distance, BF involving the non-iterative, local, and simple spatial and range kernels achieved edge preservation and image smoothing at the same time . This alIn general, the previous BF studies can be categorized as histogram-based ,15, quanChaudhury et al. used trigonometric range kernels to approximate the standard spatial Gaussian kernels of BF , which wmplexity . Based omplexity . Guo et mplexity . Similarmplexity .When BF-based methods were used in denoising, image noises cannot be differentiated from details with its range kernel once noisy pixels have large differences from their neighborhood ones, retaining most noise in the denoising result. Gaussian-Adaptive BF (GABF)  then calWe propose a novel Dual-Histogram BF (DHBF) method to achieve better denoising and edge-preserving smoothing with r is the search radius.Many local histogram generation algorithms have been presented in previous studies ,30,31,32Inspired from the integral image approach, a constant time istogram . Based oistogram . This diistogram . Peng etistogram  being apistogram .Peng et al. have demonstrated that their proposed algorithm was more efficient than other gorithms . Hence, x. x of the guidance image Let nctions: α=exlated as:Jx=∑s∈ΩxKTo keep the center pixel’s origin intensity, we replace truction  to achieEquation .As shown in To show the visual perception effects of edge-preserving image smoothing from each BF-based method, we selected one representative sample from each of the above five databases. We observed that some obvious noise artifacts still remain in the image after the BF , OFBF 22, and GAIn addition to the above qualitative analysis, we also used peak Signal-to-Noise Ratio (PSNR) , StructuThis work proposed a novel Dual-histogram Bilateral Filtering (DHBF) with the range kernel computed based on the computationally inexpensive edge-preserving guidance image to produce better denoising results than existing state-of-the-art BF methods. In contrast to the compared computational-intelligence-based BF approach, OFBF, approximating the truncated Gaussian kernel, we calculated the spatial kernel using mean filtering based on column histogram construction, both achieving


The human genome bears evidence of extensive invasion by retroviruses and other retroelements, as well as by diverse RNA and DNA viruses. High frequency of somatic integration of the RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the DNA of infected cells was recently suggested, based on a number of observations. One key observation was the presence of chimeric RNA-sequencing (RNA-seq) reads between SARS-CoV-2 RNA and RNA transcribed from human host DNA. Here, we examined the possible origin specifically of human-SARS-CoV-2 chimeric reads in RNA-seq libraries and provide alternative explanations for their origin. Chimeric reads were frequently detected also between SARS-CoV-2 RNA and RNA transcribed from mitochondrial DNA or episomal adenoviral DNA present in transfected cell lines, which was unlikely the result of SARS-CoV-2 integration. Furthermore, chimeric reads between SARS-CoV-2 RNA and RNA transcribed from nuclear DNA were highly enriched for host exonic, rather than intronic or intergenic sequences and often involved the same, highly expressed host genes. Although these findings do not rule out SARS-CoV-2 somatic integration, they nevertheless suggest that human-SARS-CoV-2 chimeric reads found in RNA-seq data may arise during library preparation and do not necessarily signify SARS-CoV-2 reverse transcription, integration in to host DNA and further transcription. Viruses hijack the host cell to replicate their RNA or DNA genomes and create progeny virions. An extreme form of viral parasitism is the integration of a viral genome DNA copy into the host cell DNA . AlthougAlu elements, rely on long interspersed nuclear elements (LINEs) for their reverse transcription and integration -retrotransposons (MaLRs) rely on endogenous retroviruses (ERVs) for their reverse-transcription and integration. Similarly, short interspersed nuclear elements (SINEs), including egration .The reverse transcriptase and endonuclease activity of LINEs, carried out by the ORF2p protein, can also mediate reverse transcription and integration of unrelated viral and non-viral RNAs . Indeed,Recent studies reported a high frequency of reverse transcription and integration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in infected cells , with imPublic RNA-seq datasets under the accession numbers GSE147507 , GSE1503Chimeric reads between human and SARS-CoV-2 RNA have been identified in RNA-seq data from infected cells in two recent studies , presumeACE2, encoding the cellular receptor for SARS-CoV-2, and A549 cells overexpressing ACE2 from an adenoviral vector, and Calu3 cells that naturally express ACE2 (GSE147507). These cells were infected with SARS-CoV-2 or with other respiratory viruses, including human parainfluenza virus type 3 (HPIV3), influenza A virus (IAV), IAV lacking the antiviral NS1 gene (IAVdNS1), and respiratory syncytial virus (RSV), or were left uninfected, and were subsequently subjected to RNA-seq  cells, A549 cells that do not normally express  RNA-seq . In addi RNA-seq . The lat RNA-seq . Lastly, RNA-seq .ACE2 (A549 ACE2 cells) and Calu3 cells showed the highest number of viral reads, with parental A549 cells and NHBE cells showing lower read numbers , whereas chimeric reads aligning to introns or intergenic regions were far fewer . Notablyvia consecutive reverse transcription reactions is indirectly supported by the presence of mtRNA-nRNA fusions in public expression sequence tags (ESTs) databases. The spatial separation of mitochondrial and nuclear DNAs negates transcriptional slippage or trans-splicing, leaving consecutive reverse transcription reactions through SHS-mediated priming as a possible cause.In addition to reverse transcription and integration of viral RNA, followed transcription of the integrated copy, several alternative mechanisms might explain formation of chimeric RNA, such as genomic rearrangements, trans-splicing, or transcriptional slippage . Howevervia SHS-mediated priming during RNA-seq library construction, we first searched for mtRNA-nRNA chimeric reads, in order to assess the frequency of SHS at the junction of artifactual chimeric reads. Between 16 and 28% of analyzed mtRNA-nRNA junctions exhibited an overlap of three or more nucleotides between mitochondrial and nuclear sequences  in the murine host can provide a source of persistent antigen for the immune system . SimilarACE2, in target cells (Detection of chimeric reads between SARS-CoV-2 RNA and human RNA could also be indicative of somatic SARS-CoV-2 integration. Since detection of such chimeric reads in RNA-seq data would require transcription of the somatic integration, it would likely underestimate the total number of integrations. The high frequency of expressed somatic SARS-CoV-2 integrations reported  was, theet cells , which wChimeric reads between nuclear DNA-transcribed RNA and SARS-CoV-2 RNA involved host genes expressed at higher than average level. This correlation may have resulted from more probable detection of the higher expressed, than lower expressed genuine chimeric fragments. Alternatively, it could result from more frequent fortuitous joining, such as during RNA-seq library preparation for example, of SARS-CoV-2 RNA reads with the most abundant host gene RNA reads in the library. In support of the latter possibility, a substantial proportion of chimeric reads displayed complementarity, often over 10 nucleotides, in the joining region. Moreover, the substantially higher contribution of exonic than intronic or intergenic host sequences to human-SARS-CoV-2 chimeric reads is consistent with formation during RNA-seq library preparation, where exonic sequences are overrepresented relative to intronic or intergenic sequences.Detection of chimeric reads between SARS-CoV-2 RNA and human RNA is one of several distinct methods previously employed to estimate somatic SARS-CoV-2 integration . Given ihttps://www.ncbi.nlm.nih.gov/geo/ under the series GSE147507, GSE150316, and GSE151803.Publicly available datasets were analyzed in this study. This data can be found at: AK analyzed the data. AK and GK wrote the manuscript. Both the authors contributed to the article and approved the submitted version.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.


Background and Objectives Whether exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may predispose to the risk of cancer in individuals with no prior cancers is a crucial question that remains unclear. To confirm/refute possible relationships between exposure to the virus and ex novo insurgence of tumors, this study analyzed molecular mimicry and the related cross-reactive potential between SARS-CoV-2 spike glycoprotein (gp) antigen and human tumor-suppressor proteins.Materials and Methods Tumor-associated proteins were retrieved from UniProt database and analyzed for pentapeptide sharing with SARS-CoV-2 spike gp by using publicly available databases.Results An impressively high level of molecular mimicry exists between SARS-CoV-2 spike gp and tumor-associated proteins. Numerically, 294 tumor-suppressor proteins share 308 pentapeptides with the viral antigen. Crucially, the shared peptides have a relevant immunologic potential by repeatedly occurring in experimentally validated epitopes. Such immunologic potential is of further relevancy in that most of the shared peptides are also present in infectious pathogens to which, in general, human population has already been exposed, thus indicating the possibility of immunologic imprint phenomena.Conclusion This article described a vast peptide overlap between SARS-CoV-2 spike gp and tumor-suppressor proteins, and supports autoimmune cross-reactivity as a potential mechanism underlying prospective cancer insurgence following exposure to SARS-CoV-2. Clinically, the findings call for close surveillance of tumor sequelae that possibly could result from the current coronavirus pandemic. From lung damages to skin diseases and excessive immune responses, the disorders associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that is, coronavirus disease 2019 (COVID-19), are progressively being defined and diagnostically cataloged.According to the research paradigm that peptide sequences common to pathogens and the human host may lead to autoimmunity through cross-reactivity,Hence, this study was undertaken to further explore the relationship between SARS-CoV-2 infection/active immunization and carcinogenesis, and specifically focused on the amino acid (aa) sequence identities between SARS-CoV-2 spike glycoprotein (gp) and tumor-suppressor human proteins. Analyses revealed a vast peptide sharing potentially able to generate pathogenic autoantibodies via cross-reactivity and immunologic imprinting phenomena, thus possibly leading to or enhancing the onset of a wide spectrum of cancer diseases.www.uniprot.org)Peptide sharing between SARS-CoV-2 spike gp  and cancer-related human proteins was analyzed using pentapeptides as sequence probes as already described.Bordetella pertussis,Corynebacterium diphtheriae,Clostridium tetani,Haemophilus influenzae, andNeisseria meningitides. The publicly available peptide match and peptide search programs (www.uniprot.org) were used.Methodologically, the spike gp primary sequence was dissected into pentapeptides offset by one residue  and the resulting viral pentapeptides were analyzed for occurrences within the human proteins related to cancer. The shared peptides were also controlled for occurrences in the pathogenswww.iedb.org)The immunologic potential of the peptides shared between SARS-CoV-2 spike gp and cancer-related proteins was investigated by searching the Immune Epitope Database directly related to tumor-suppressor activity and listed inThe gloomy outlook hinted at by the findings described inIn essence,Bordetella pertussis,C. diphtheriae,C. tetani,H. influenzae, andN. meningitides(The 29 pentapeptides common to SARS-CoV-2 spike gp and tumor-suppressor proteins  are notgitides. That iSuch interpathogen peptide commonality introduces the immunologic memory as a factor capable of enhancing the extent of the immune cross-reactive response against the tumor-suppressor proteins. That is, as already described since 1947,The immunologic imprint phenomenon has its molecular foundations in the massive peptide sharing that characterizes microbial and human proteinsThe findings described in