Emergence Of New Mutations Research Articles

Sensitive Detection of Gynecological Cancer Recurrence Using Circulating Tumor DNA and Digital PCR: A Comparative Study with Serum Biochemical Markers

Early detection of recurrences in gynecological cancers is crucial for women’s health. Circulating tumor DNA (ctDNA) analysis through liquid biopsy offers a promising approach for monitoring disease progression and identifying relapses. This study investigated the utility of digital Polymerase Chain Reaction (dPCR) for ctDNA detection in three gynecological cancer patients with clinically confirmed relapses during a two-year post-surgical follow-up. Patient-specific tumor mutations were identified through whole-exome sequencing (WES) and confirmed via Sanger sequencing. dPCR probes targeting these mutations were used to quantify the ctDNA levels in plasma samples collected throughout the follow-up period, and the findings were compared with standard serum biochemical markers. In two patients, persistent positive dPCR signals for the selected mutations were detected after tumor removal, with ctDNA levels progressively increasing even after post-surgical chemotherapy. Notably, dPCR identified elevated ctDNA levels before an increase in the cancer antigen 125 (CA125) biochemical marker was observed. In the third patient, no ctDNA signals from the two selected mutations were detected despite clinical evidence of recurrence, suggesting the emergence of new mutations. While this study highlights the promise of dPCR for early recurrence detection in gynecological cancers, it also underscores the critical need for comprehensive mutation panels to overcome the inherent challenges posed by tumor heterogeneity and the emergence of new mutations during disease progression.

Update on Mpox Management: Epidemiology, Vaccines and Therapeutics, and Regulatory Changes.

Mpox, caused by the monkeypox virus (MPXV), is categorized into two primary clades: Clade I and Clade II, with notable outbreaks linked to Clade IIb. Historically endemic in Africa, recent years have seen significant global spread. The World Health Organization (WHO) declared mpox a Public Health Emergency of International Concern in August 2024, highlighting the emergence of Clade Ib outside Africa and the broadening demographic impact of the outbreak. This review updates the current status of mpox vaccines and treatments, including their safety and effectiveness. There are two US Food and Drug Administration (FDA)-approved vaccines for the prevention of mpox disease, JynneosTM and ACAM2000®. The JynneosTM vaccine, recommended for high-risk individuals, has seen limited uptake despite its efficacy in preventing disease. Tecovirimat, while FDA-approved for smallpox and available in the European Union for mpox, has shown mixed results in recent trials, with new data suggesting limited effectiveness in Clade I infections and emergence of new mutations with resistance to this drug. Brincidofovir and Vaccinia Immune Globulin Intravenous offer additional treatment options, particularly for severe cases, although their use is constrained by regulatory and logistical challenges. Furthermore, the WHO recently approved the first commercial molecular assay, the Alinity m MPXV assay by Abbott Molecular Inc., for emergency use-an essential step in expanding testing capacity in regions experiencing mpox outbreaks. These updates underscore the critical need for continued research to enhance therapeutic outcomes and adapt public health strategies. Ensuring equitable access to vaccines, treatments, and diagnostics remains a significant challenge as the global community responds to the evolving mpox situation.

Customised design of antisense oligonucleotides targeting EGFR driver mutants for personalised treatment of non-small cell lung cancer

Tyrosine kinase inhibitors (TKIs) are currently the standard therapy for patients with non-small cell lung cancer (NSCLC) bearing mutations in epidermal growth factor receptor (EGFR). Unfortunately, drug-acquired resistance is inevitable due to the emergence of new mutations in EGFR. Moreover, the TKI treatment is associated with severe toxicities due to the unspecific inhibition of wild-type (WT) EGFR. Thus, treatment that is customised to an individual's genetic alterations in EGFR may offer greater therapeutic benefits for patients with NSCLC. In this study, we demonstrate a new therapeutic strategy utilising customised antisense oligonucleotides (ASOs) to selectively target activating mutations in the EGFR gene in an individualised manner that can overcome drug-resistant mutations. We use extracellular vesicles (EVs) as a vehicle to deliver ASOs to NSCLC cells. Specifically guided by the mutational profile identified in NSCLC patients, we have successfully developed ASOs that selectively inhibit point mutations in the EGFR gene, including L858R and T790M, while sparing the WT EGFR. Delivery of the EGFR-targeting ASOs by EVs significantly reduced tumour growth in xenograft models of EGFR-L858R/T790M-driven NSCLC. Importantly, we have also shown that EGFR-targeting ASOs exhibit more potent anti-cancer effect than TKIs in NSCLC with EGFR mutations, effectively suppressing a patient-derived TKI-resistant NSCLC tumour. Overall, by harnessing the specificity and efficacy of ASOs, we present an effective and adaptable therapeutic platform for NSCLC treatment. This study was funded by Singapore's Ministry of Health (NMRC/OFIRG/MOH-000643-00, OFIRG21nov-0068, NMRC/OFLCG/002-2018, OFYIRG22jul-0034), National Research Foundation (NRF-NRFI08-2022, NRF-CRP22-2019-0003, NRF-CRP23-2019-0004), A∗STAR, and Ministry of Education.

Dynamic clade transitions and the influence of vaccination on the spatiotemporal circulation of SARS-CoV-2 variants

Since 2021, the emergence of variants of concern (VOC) has led Brazil to experience record numbers of in COVID-19 cases and deaths. The expanded spread of the SARS-CoV-2 combined with a low vaccination rate has contributed to the emergence of new mutations that may enhance viral fitness, leading to the persistence of the disease. Due to limitations in the real-time genomic monitoring of new variants in some Brazilian states, we aimed to investigate whether genomic surveillance, coupled with epidemiological data and SARS-CoV-2 variants spatiotemporal spread in a smaller region, can reflect the pandemic progression at a national level. Our findings revealed three SARS-CoV-2 variant replacements from 2021 to early 2022, corresponding to the introduction and increase in the frequency of Gamma, Delta, and Omicron variants, as indicated by peaks of the Effective Reproductive Number (Reff). These distinct clade replacements triggered two waves of COVID-19 cases, influenced by the increasing vaccine uptake over time. Our results indicated that the effectiveness of vaccination in preventing new cases during the Delta and Omicron circulations was six and eleven times higher, respectively, than during the period when Gamma was predominant, and it was highly efficient in reducing the number of deaths. Furthermore, we demonstrated that genomic monitoring at a local level can reflect the national trends in the spread and evolution of SARS-CoV-2.

Unraveling the Progression of Colon Cancer Pathogenesis Through Epigenetic Alterations and Genetic Pathways.

In the modern age, colon cancer has attained a widespread status, affecting a considerable number of people.It develops due to the progressive accumulation of genetic and epigenetic alterations. While genetic mutations have been extensively studied in the context of colon cancer, emerging evidence highlights the pivotal role of epigenetic alterations in its pathogenesis. These alterations ultimately result in the transformation of normal colonic epithelium into colon adenocarcinoma.Key mechanisms of epigenetic modifications include DNA methylation, histone modification, and nucleosome positioning. Research findings have linked these modifications to the development, progression, or metastasis of tumors. Through the assessment of the colon cancer epigenome,it has been discovered that practically all colorectal cancers (CRCs) display gene methylation abnormalities and changes in miRNA expression. Advancements in this area indicate that epigenetic modifications will likely be commonly used in the near future to direct the prevention and treatment of CRC. The maintenance of genome stability is essential for preserving cellular integrity. The development of CRC is primarily influenced by the loss of genomic stability, which allows for the emergence of new mutations contributing to tumor characteristics. Although genetic mutations have been extensively researched in the realm of colon cancer, recent evidence underscores the pivotal role of epigenetic changes in its pathogenesis. The following types of genomic instability will be discussed: chromosomal instability, microsatellite instability, CpG island methylation phenotype, and aberrant DNA methylation.

The AI ethics of digital COVID-19 diagnosis and their legal, medical, technological, and operational managerial implications

The COVID-19 pandemic has given rise to a broad range of research from fields alongside and beyond the core concerns of infectiology, epidemiology, and immunology. One significant subset of this work centers on machine learning-based approaches to supporting medical decision-making around COVID-19 diagnosis. To date, various challenges, including IT issues, have meant that, notwithstanding this strand of research on digital diagnosis of COVID-19, the actual use of these methods in medical facilities remains incipient at best, despite their potential to relieve pressure on scarce medical resources, prevent instances of infection, and help manage the difficulties and unpredictabilities surrounding the emergence of new mutations. The reasons behind this research-application gap are manifold and may imply an interdisciplinary dimension. We argue that the discipline of AI ethics can provide a framework for interdisciplinary discussion and create a roadmap for the application of digital COVID-19 diagnosis, taking into account all disciplinary stakeholders involved. This article proposes such an ethical framework for the practical use of digital COVID-19 diagnosis, considering legal, medical, operational managerial, and technological aspects of the issue in accordance with our diverse research backgrounds and noting the potential of the approach we set out here to guide future research.

In silico analysis of non-structural protein 12 sequences from SARS-COV-2 found in Manaus, Amazonas, Brazil, reveals mutations linked to higher transmissibility.

The disease coronavirus COVID-19 has been the cause of millions of deaths worldwide. Among the proteins of SARS-CoV-2, non-structural protein 12 (NSP12) plays a key role during COVID infection and is part of the RNA-dependent RNA polymerase complex. The monitoring of NSP12 polymorphisms is extremely important for the design of new antiviral drugs and monitoring of viral evolution. This study analyzed the NSP12 mutations detected in circulating SARS-CoV-2 during the years 2020 to 2022 in the population of the city of Manaus, Amazonas, Brazil. The most frequent mutations found were P323L and G671S. Reports in the literature indicate that these mutations are related to transmissibility efficiency, which may have contributed to the extremely high numbers of cases in this location. In addition, two mutations described here (E796D and R914K) are close and have RMSD that is similar to the mutations M794V and N911K, which have been described in the literature as influential on the performance of the NSP12 enzyme. These data demonstrate the need to monitor the emergence of new mutations in NSP12 in order to better understand their consequences for the treatments currently used and in the design of new drugs.

Redox-Active Cerium Fluoride Nanoparticles Selectively Modulate Cellular Response against X-ray Irradiation In Vitro.

Ionizing radiation-induced damage in cancer and normal cells leads to apoptosis and cell death, through the intracellular oxidative stress, DNA damage and disorders of their metabolism. Irradiation doses that do not lead to the death of tumor cells can result in the emergence of radioresistant clones of these cells due to the rearrangement of metabolism and the emergence of new mutations, including those in the genes responsible for DNA repair. The search for the substances capable of modulating the functioning of the tumor cell repair system is an urgent task. Here we analyzed the effect of cerium(III) fluoride nanoparticles (CeF3 NPs) on normal (human mesenchymal stem cells-hMSC) and cancer (MCF-7 line) human cells after X-ray radiation. CeF3 NPs effectively prevent the formation of hydrogen peroxide and hydroxyl radicals in an irradiated aqueous solution, showing pronounced antioxidant properties. CeF3 NPs are able to protect hMSC from radiation-induced proliferation arrest, increasing their viability and mitochondrial membrane potential, and, conversely, inducing the cell death of MCF-7 cancer cells, causing radiation-induced mitochondrial hyperpolarization. CeF3 NPs provided a significant decrease in the number of double-strand breaks (DSBs) in hMSC, while in MCF-7 cells the number of γ-H2AX foci dramatically increased in the presence of CeF3 4 h after irradiation. In the presence of CeF3 NPs, there was a tendency to modulate the expression of most analyzed genes associated with the development of intracellular oxidative stress, cell redox status and the DNA-repair system after X-ray irradiation. Cerium-containing nanoparticles are capable of providing selective protection of hMSC from radiation-induced injuries and are considered as a platform for the development of promising clinical radioprotectors.

HLA-DQ2/8 and COVID-19 in Celiac Disease: Boon or Bane.

The SARS-CoV-2 pandemic continues to pose a global threat. While its virulence has subsided, it has persisted due to the continual emergence of new mutations. Although many high-risk conditions related to COVID-19 have been identified, the understanding of protective factors remains limited. Intriguingly, epidemiological evidence suggests a low incidence of COVID-19-infected CD patients. The present study explores whether their genetic background, namely, the associated HLA-DQs, offers protection against severe COVID-19 outcomes. We hypothesize that the HLA-DQ2/8 alleles may shield CD patients from SARS-CoV-2 and its subsequent effects, possibly due to memory CD4 T cells primed by previous exposure to human-associated common cold coronaviruses (CCC) and higher affinity to those allele's groove. In this context, we examined potential cross-reactivity between SARS-CoV-2 epitopes and human-associated CCC and assessed the binding affinity (BA) of these epitopes to HLA-DQ2/8. Using computational methods, we analyzed sequence similarity between SARS-CoV-2 and four distinct CCC. Of 924 unique immunodominant 15-mer epitopes with at least 67% identity, 37 exhibited significant BA to HLA-DQ2/8, suggesting a protective effect. We present various mechanisms that might explain the protective role of HLA-DQ2/8 in COVID-19-afflicted CD patients. If substantiated, these insights could enhance our understanding of the gene-environment enigma and viral-host relationship, guiding potential therapeutic innovations against the ongoing SARS-CoV-2 pandemic.

Clonal Dynamics of FLT3-ITD Positive Acute Myeloid Leukemia Patients with Relapsed/Refractory Disease Following Intensive Chemotherapy +/- Midostaurin

Introduction: Despite the wider use of midostaurin (MIDO) in combination with intensive chemotherapy (ICT) as the 1st-line treatment for FLT3-mutated acute myeloid leukemia (AML), complete remission (CR) rates are close to 60%, and relapses occur in over 40% of cases, demonstrating the ability of leukemic cells to resist and evade therapy ( Stone et al., NEJM 2017). Conventional fragment-length analyses of paired diagnosis/relapse samples have shown that FLT3-internal tandem duplications (ITDs) are retained in 80% and 50% of cases following ICT alone and MIDO+ICT respectively ( Schmalbrock et al., Blood 2021). Only limited data are available on the dynamics of FLT3-ITDs or other co-mutations in refractory patients (pts). Here, we conducted a retrospective study involving 115 pts with relapsed/refractory AML harboring FLT3-ITD at diagnosis. Materials and methods: Clonal evolution was examined in paired diagnosis/progression blood or bone marrow samples from 115 pts with FLT3-ITD+ AML treated with MIDO+ICT (n=33) or ICT alone (n=82). Among them, 21 pts had primary refractory disease (MIDO+ICT, n=8; ICT, n=13) and 94 pts relapsed after achieving CR (MIDO+ICT, n=25; ICT, n=69). FLT3-ITDs and co-mutations were screened on genomic DNA by high-throughput sequencing at both timepoints using a custom-designed panel. For accurate annotation and quantification of FLT3-ITDs from sequencing data, we used the recentlypublished FiLT3r algorithm ( Boudry et al., BMC Bioinformatics 2022). For each ITD detected, FiLT3r allelic ratio (AR) was assessed by the ratio between the mutated allele and the wild-type allele. Results: A total of 226 FLT3-ITDs were detected in 115 pts at AML diagnosis, among which 120 (53%) ITDs were found with an AR below 0.05 ( Figure 1). Among pts who achieved CR and experienced relapse (n=94), 48 had multiple FLT3-ITDs at diagnosis and 46 had a single FLT3-ITD at diagnosis. Overall, we observed a simplification of the FLT3-ITD repertoire upon relapse with the persistence of at least one initial clone in 8/12 [67%] and 24/36 [67%] pts with multiple ITDs receiving MIDO+ICT and ICT alone respectively. In relapsed pts who initially had a single FLT3-ITD clone at diagnosis, the addition of MIDO to ICT was associated with a higher rate of FLT3-ITD negativity compared to pts receiving ICT alone (6/13 [46%] vs 5/33 [15%]; P = 0.05) ( Figure 2). Interestingly, among 21 pts with primary refractory AML, we observed that FLT3-ITD mutation status became negative in 5/8 pts (62%) and 2/13 pts (15%) after induction with MIDO+ICT and ICT alone respectively. We then compared the initial characteristics between retained and lost FLT3-ITDs at AML relapse. Lost FLT3-ITDs had significantly lower AR than retained clones in both treatment groups. In order to limit the impact of sample dilution on the allele burden, we defined adjusted variant allele frequencies (VAFs) as the VAFs of FLT3-ITDs normalized to the VAFs of NPM1 mutations, whenever applicable. In so doing, we observed that adjusted VAFs of retained FLT3-ITDs increased at relapse, regardless of the treatment group (adjusted VAF, diagnosis vs relapse: 0.28 vs 0.86 and 0.88 vs 1.6 in the MIDO+ICT group and ICT alone group; P = 2.3e-03 and P = 2.4e-04). Importantly, an adjusted VAF higher than 1 was strongly suggestive of a homozygous state of FLT3-ITD. Such situation was found to be more prevalent at relapse in both treatment groups. Besides the selection of a dominant FLT3-ITD clone, other relapse-related changes including the acquisition of additional mutations will be presented. Conclusion: Our study of the clonal dynamics of AML with FLT3-ITD mutations provides insights into the mechanisms underlying therapy escape. Our data suggest that clonal interference characterized by multiple FLT3-ITD clones is associated with a greater ability to select a FLT3-ITD-positive clone at relapse in pts receiving MIDO+ICT. Although the addition of MIDO to ICT increases the probability of eradicating a single FLT3-ITD clone, FLT3-ITD+ relapses remain common following this combination, often with the selection of homozygous FLT3-ITD clones and/or the emergence of new mutations. Finally, our data in refractory situation emphasize the need to reassess mutational status at each stage of progression before implementing targeted therapy.

Molecular Response Analysis By High Throughput Sequencing in Higher Risk Myelodysplastic Syndrome (HR-MDS) Treated Intensively with CPX-351

Context and objective Intensive chemotherapy (IC) remains an important therapeutic option in HR-MDS, but in-depth evaluation of response to IC remains ill studied. We previously reported results of CPX-351 in 31 untreated higher risk MDS patients (pts) (GFM-CPX-MDS study, NCT04273802, ASH 2021 Abst #243). Responses were associated with a significant decrease of CD34/CD117 progenitors and restoration of normal hematopoiesis patterns in bone marrow (BM) samples in multiparameter flow cytometry. In this ancillary study, the aim was to evaluate molecular responses by high-throughput sequencing (HTS) centrally. This involved description of the pts molecular landscape and an assessment of variant allele frequency (VAF) variations after induction treatment with CPX-351. Methods The mutational landscape was explored in BM nuclear cells by capture HTS of 42 genes (SureSelect XTHS2 Agilent) with unique molecular identifiers (UMI), unique dual index (UDI) and Illumina paired-end sequencing (Miseq and Nextseq). Somatic mutations (SM) were considered significant for VAFs >2%. Molecular response was evaluated by comparing baseline and post-induction. Molecular clearance was defined according to (i) clearance (<2%) of all SM excluding the "pre-leukemic” SM of DNMTA, TET2, ASXL1 (DTA) (ii) clearance of all non-DTA SM < HTS detection threshold (iii) normalized VAF decrease of the major non-DTA baseline SM (nmVAF). Results Median age of the 31 pts included was 62 years (range 31-69). There were 26 MDS-EB2 and 5 CMML-2. IPSS was int-2 in 26 pts and high in 5. Cytogenetic IPSS-R was very good (6.5%), good (71%, including normal in 22 pts), int (9.5%), poor (6.5%) or very poor (6.5%). After induction with CPX-351 (3 days cycle and a possible 2-day second induction cycle for non-responders), 16 pts (52%) reached CR, 4 (13%) CRi, 7 (22%) MLFS while 4 (13%) were in stable disease according to ELN 2017 criteria (which appeared more adequate than MDS IWG 2006, as reported at ASH 2021, Abst #243). Median follow-up was 511 days (179-710), 29/31 patients (94%) received allogeneic hematopoietic stem cell transplantation (Allo-HSCT) after, no, 1, 2, 3 or 4 CPX-351 consolidation cycles (that included only 1 day of CPX-351) in 10, 16, 7, 3 and 1 patients respectively. So far, 4 relapses have occurred, including 3 in transplanted pts. At inclusion, all pts had at least one mutation (median 3, [1-14]) with a mean VAF of 30% (2-89), implicating at least one DTA (71%; 22/31) or one non-DTA genes (93%; 29/31) (fig). Very high or high risk was seen in 19/31 (61%) pts according to the new IPSSm classification. Post induction molecular response was evaluated at a median of 53 days from CPX-351 onset (28-112) in 26 of the 27 who reached at least MLFS, and had a post-induction sample. Molecular clearance was observed (i) at the 2% threshold of non-DTA genes in 17/26 (65%) pts (ii) at the HTS detection threshold (0.1% i.e. minimum considered 3X with median coverage > 3000X) in 11/26 pts (42%) (iii) by nmVAF decrease in 25/26 pts (96%) with a median of -62% (-2 to -100%) (fig) while the remaining pt had an increase of SRSF2 (+67%) and RUNX1 (+46%) SMs but disappearance of three STAG2 SMs and was still in CR after allogeneic SCT. Of note, DTA SMs remained detectable in all pts with a median nmVAF modulation of -86% (+83% to -99.6%, fig) from baseline to post-induction. Of the 4 non-responders to CPX-351, 2 had high risk anomalies (inv(3) and EZH2 / RUNX1 SMs). The 3 relapses observed after alloHSCT, at 7, 8 and 15 months had nmVAFs decrease from baseline to post-induction of -95%, -98% and -50% respectively. Among them, one had a very complex karyotype and a homozygous TP53 mutation, the two others had a high mutational load and EZH2 mutations and one of the latest was transplanted in refractory state. Clonal evolution was observed in 5/26 pts with significant emergence of new mutations involving PPM1D, ASXL1 or JAK2 and in one pt the emergence of EZH2, RUNX1 and TET2 SMs. Four of these pts remained in morphological CR while one progressed to AML. Conclusion In 25/26 CPX-351 responders, a significant decrease of nmVAF was observed, confirming the interest of CPX-351 treatment in higher risk MDS, especially as a bridge to transplant. Follow up is ongoing and few relapses were seen to evaluate the predictive role of molecular analysis. An update will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Perioperative treatment and biomarker analysis of LP002, an anti-PD-L1 antibody, plus chemotherapy in resectable gastric and gastroesophageal junction cancer.

The addition of immune checkpoint inhibitors to perioperative chemotherapy in operable gastric or gastroesophageal junction (GEJ) cancer has become one of the research hotspots, while reliable biomarkers for efficacy are lacking. We conducted a phase 1 trial to assess the safety and efficacy of LP002, an anti-PD-L1 antibody, plus chemotherapy as perioperative treatment in patients with gastric or GEJ cancer. We enrolled patients with resectable and PD-L1 positive gastric or GEJ cancers. Eligible patients received three preoperative and six postoperative cycles of intravenous LP002 with cisplatin and 5-fluorouracil, repeated every 2 weeks. The primary endpoint was safety. Secondary endpoints included rate of margin-free (R0) resection and pathological complete response (pCR). We also characterized changes in the tumor immune microenvironment using multiplex immunofluorescence (MIF) staining and next-generation sequencing (NGS) with pre- and post-treatment tumor samples. Thirty patients were enrolled, of whom 28 had GEJ cancer. With a median follow-up of 7.9 months, all patients completed preoperative treatment, and 27 patients underwent surgery. Twenty-four patients underwent R0 resection. Six patients (20.0%) had Mandard tumor regression grade (TRG) 1-3, including one achieving pCR. Twenty-seven patients had treatment-related adverse events (TRAEs), while grade 3-4 TRAEs were observed in 11 patients. No treatment-related deaths occurred. MIF staining revealed that TRG 1-3 group was associated with a higher density of PD-L1+/CD68+ cells in the pre-treatment tumor parenchyma than TRG 4-5 group (p=0.048). NGS studies with paired pre- and post-treatment tumor samples revealed the disappearance of pre-existing mutations, the emergence of new mutations, and variations in the abundance of mutations after preoperative LP002 and chemotherapy. Meanwhile, tumor mutational burden decreased in patients with TRG 1-3 (p=0.0313). LP002 plus cisplatin and 5-fluorouracil are safe in patients with gastric or GEJ cancer, and patient selection via appropriate biomarkers is needed in the future.

Modulating the Expression of Multiple Surface Receptors on Epithelial Cells and Promoting Lung Macrophage Anti-viral Functions by OM-85 Inhibits Severe Acute Respiratory Syndrome Coronavirus 2 Infection

The emergence of a new virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, in December 2019 triggered a global pandemic, forcing much of the world to adopt lockdown strategies and leading to extraordinary threats to the global healthcare system. The clinical manifestations of the disease, referred to as COVID-19, range from mild, self-limiting flu-like respiratory illness to life-threatening multi-organ failure and death. The rapid progress in our understanding of COVID-19 pathogenesis has led the development of effective vaccines, monoclonal antibodies, and anti-viral agents. However, a major cause of concern is the continuous and rapid emergence of new mutations that can progressively decrease sensitivity to the existing anti-COVID-19 tools. Safe, affordable, and widely available treatments are therefore urgently needed to reduce the frequency and/or severity of SARS-CoV-2 infection. OM-85 is a standardised lysate of bacterial strains widely used for the prophylaxis of airway recurrent infections in adults and children with an excellent safety profile. In experimental animal models and in clinical trials this compound was shown to possess anti-viral activities through immunomodulatory responses, but also by inhibiting infection. The positive results reported in models of common respiratory virus infection has recently encouraged researchers from three independent groups to evaluate whether OM-85 could also affect SARS-CoV-2 infection. The results of these studies are summarised in this review.

Asciminib as a third line option in chronic myeloid leukemia.

Unmet needs remain in the treatment of chronic phase chronic myeloid leukemia (CML) in later lines. Sequential use of tyrosine kinase inhibitors (TKIs) is associated with decreased overall survival and emergence of new mutations, particularly the T315I mutation. Among the new drugs developed to overcome resistance and intolerance, the STAMP inhibitor asciminib (which specifically targets the ABL myristoyl pocket) is the first example of a drug that works by allosteric inhibition. This review focuses on its mechanism of action, pharmacokinetic, efficacy, and toxicity, as well as how this drug will change the therapeutic approach for CML patients not eligible to receive other available drugs.

Immune Escape Associated with RBD Omicron Mutations and SARS-CoV-2 Evolution Dynamics.

The evolution and the emergence of new mutations of viruses affect their transmissibility and/or pathogenicity features, depending on different evolutionary scenarios of virus adaptation to the host. A typical trade-off scenario of SARS-CoV-2 evolution has been proposed, which leads to the appearance of an Omicron strain with lowered lethality, yet enhanced transmissibility. This direction of evolution might be partly explained by virus adaptation to therapeutic agents and enhanced escape from vaccine-induced and natural immunity formed by other SARS-CoV-2 strains. Omicron’s high mutation rate in the Spike protein, as well as its previously described high genome mutation rate (Kandeel et al., 2021), revealed a gap between it and other SARS-CoV-2 strains, indicating the absence of a transitional evolutionary form to the Omicron strain. Therefore, Omicron has emerged as a new serotype divergent from the evolutionary lineage of other SARS-CoV-2 strains. Omicron is a rapidly evolving variant of high concern, whose new subvariants continue to manifest. Its further understanding and the further monitoring of key mutations that provide virus immune escape and/or high affinity towards the receptor could be useful for vaccine and therapeutic development in order to control the evolutionary direction of the COVID-19 pandemic.

Analysis of airborne sputum droplets flow dynamic behaviors under different ambient conditions and aerosol size effects

The coronavirus (COVID-19) is becoming more threatening with the emergence of new mutations. New virus transmission and infection processes remain challenging and re-examinations of proper protection methods are urgently needed. From fluid dynamic viewpoint, the transmission of virus-carrying droplets and aerosols is one key to understanding the virus-transmission mechanisms. This study shows virus transmission by incorporating flow-evaporation model into the Navier-Stokes equation to describe the group of airborne sputum droplets exhaled under Rosin-Rammler distribution. Solid components and humidity field evolution are incorporated in describing droplet and ambient conditions. The numerical model is solved by an inhouse code using advection-diffusion equation for the temperature field and the humidity field, discretized by applying the total-variation diminishing Runge-Kutta method. The results of this study are presented in detail to show the different trends under various ambient conditions and to reveal the major viral-transmission routes as a function of droplet size.

Effectiveness of Coronavirus Disease 2019 Vaccines in Preventing Infection, Hospital Admission, and Death: A Historical Cohort Study Using Iranian Registration Data During Vaccination Program.

BackgroundThere are some concerns about the effectiveness of the inactivated and vector-based vaccines against severe acute respiratory syndrome coronavirus 2 in real-world settings with the emergence of new mutations, especially variants of concern. Data derived from administrative repositories during mass vaccination campaigns or programs are of interest to study vaccine effectiveness.MethodsUsing 4-repository administrative data linkage, we conducted a historical cohort study on a target population of 1 882 148 inhabitants aged at least 18 years residing in southern Iran.ResultsWe estimated a 71.9% [95% confidence interval [CI], 70.7%–73.1%], 81.5% [95% CI, 79.5%–83.4%], 67.5% [95% CI, 59.5%–75.6%], and 86.4% [95% CI, 84.1%–88.8%] hospital admission reduction for those who received the full vaccination schedule of BBIBP-CorV (Sinopharm), ChAdOx1-S/nCoV-19 vaccine (AZD1222, Oxford-AstraZeneca), rAd26-rAd5 (Gam-COVID-Vac, Sputnik V), and BIV1-CovIran (COVIran Barekat) vaccines, respectively. A high reduction in mortality (at least 85%) was observed in all age subgroups of the fully immunized population.ConclusionsThe pragmatic implementation of a vaccination plan including all available vaccine options in the Iranian population was associated with a significant reduction in coronavirus disease 2019 (COVID-19) detected infections as well as hospital admissions and deaths associated with COVID-19.

Stem Cell-based therapies for COVID-19-related acute respiratory distress syndrome.

As the number of confirmed cases and resulting death toll of the COVID‐19 pandemic continue to increase around the globe ‐ especially with the emergence of new mutations of the SARS‐CoV‐2 virus in addition to the known alpha, beta, gamma, delta and omicron variants ‐ tremendous efforts continue to be dedicated to the development of interventive therapeutics to mitigate infective symptoms or post‐viral sequelae in individuals for which vaccines are not accessible, viable or effective in the prevention of illness. Many of these investigations aim to target the associated acute respiratory distress syndrome, or ARDS, which induces damage to lung epithelia and other physiologic systems and is associated with progression in severe cases. Recently, stem cell‐based therapies have demonstrated preliminary efficacy against ARDS based on a number of preclinical and preliminary human safety studies, and based on promising outcomes are now being evaluated in phase II clinical trials for ARDS. A number of candidate stem cell therapies have been found to exhibit low immunogenicity, coupled with inherent tropism to injury sites. In recent studies, these have demonstrated the ability to modulate suppression of pro‐inflammatory cytokine signals such as those characterizing COVID‐19‐associated ARDS. Present translational studies are aiming to optimize the safety, efficacy and delivery to fully validate stem cell‐based strategies targeting COVID‐19 associated ARDS for viable clinical application.

Abstract P1-08-27: Dynamic monitoring of circulating tumor DNA can predict chemotherapy response and prognosis in metastatic triple-negative breast cancer patients

Abstract Background: Chemotherapy is the main treatment for metastatic triple-negative breast cancer (mTNBC). However, mTNBC patients (pts) is often associated with chemotherapy resistance and poor prognosis. Biomarkers that can effectively predict the efficacy of chemotherapy for mTNBC are currently lacking. Detection of circulating tumor DNA (ctDNA) in plasma by liquid biopsy is a minimally invasive and highly sensitive method, which has been wildly used in the clinic and plays an important role in tumor diagnosis, efficacy evaluation, residual and recurrent tumor detection, etc. But yet, the clinical application of ctDNA in mTNBC remains relatively scarce. Here, for the first time, we set to explore the possibility of ctDNA as a biomarker for predicting chemotherapy response and prognosis in mTNBC.Methods: From May 2018 to October 2020, 38 mTNBC pts who received less than 3rd line standard chemotherapy were prospectively included. Tumor tissues were obtained prior chemotherapy, and plasma for ctDNA were collected at baseline, a day before the 3rd cycle chemotherapy and at disease progression. Next-generation sequencing (NGS,457 genes panel) was performed on all samples for mutation detection. And the ctDNA fraction, maximum variant allele frequency (max-VAF), tumor mutation burden (TMB) and other variate were calculated, further combined with clinical data, chemotherapy response and survival of pts for statistical analysis.Results: Finally, 109 blood samples and 13 tissue samples were detected by NGS. A total of 214 mutation genes and 397 mutation sites were detected. The mutation types included missense mutation, nonsense mutation, non-/frameshift insertion, non-/frameshift deletion, non-/frameshift substitution, splicing mutation and so on. The genes with the top 5 mutation frequencies were TP53 (32/38, 84.21%), PIK3CA (14/38, 36.84%), KMT2C (8/38, 21.05%), PTEN (6/38, 15.79%), NOTCH4 (6/38, 15.79%), respectively. The same variants were identified in 12 of 13 pts in paired plasma and tissue, with a concordance rate of 92.3%. The mutation rate in plasma ctDNA was significantly lower than that in tissues (15.26% ± 12.52% vs. 28.88 ± 16.54%, P &amp;lt; 0.001) but was still positively correlated with that in tissues (r = 0.306, P = 0.049). The median progression-free survival (mPFS) of pts with GNAS mutation was shorter than GNAS wild-type pts (3.000 vs. 6.100 months, P = 0.014). The area under curve of ctDNA fraction (0.812, P = 0.043), max-VAF (0.817, P = 0.043) and TMB (plasma) (0.759, P = 0.053) in predicting chemotherapy resistance or disease progression were larger than CEA (0.491, P = 0.888), CA125 (0.574, P = 0.243) and CA153 (0.482, P = 0.778). CtDNA fraction (r = 0.482, P &amp;lt; 0.001), max-VAF (r = 0.489, P &amp;lt; 0.001), TMB (plasma). (r = 0.419, P &amp;lt; 0.001) were correlated with chemotherapy response measured by RECIST v1.1 in CT imaging, while CEA (r = -0.024, P = 0.808), CA125 (r = 0.111, P = 0.266) and CA153 (r = -0.017, P = 0.865) had no correlation with chemotherapy response. The mPFS of pts with ctDNA fraction ≤ 50% or max-VAF ≤ 0.4 at baseline was significantly longer than that of pts with ctDNA fraction &amp;gt; 50% (6.100 vs. 3.430 months, P = 0.006) or max-VAF &amp;gt; 0.4 (6.100 vs. 3.430 months, P = 0.047). The elimination of mutations or the decrease of mutation rate in plasma ctDNA after 2 cycles of chemotherapy showed better chemotherapy response, while recurrence of mutations, increase of mutation rate and emergence of new mutations showed chemotherapy resistance.Conclusions: Mutations in tumor tissues and plasma ctDNA of mTNBC pts detected by NGS have high consistency. And compared with CT imaging and traditional tumor markers, dynamic monitoring ctDNA can more aptly reflect the change of whole-body tumor burden, better predict the chemotherapy response and prognosis in mTNBC. Citation Format: Huihui Li, Yajing Chi, Sha Yin, Bo Yu, Mu Su, Baoxuan Zhang, Ling Qiang, Guohua Ren, Lihua Song, Bing Bu, Shu Fang, Mao Shang, Qiaorui Tan, Xiaochu Man. Dynamic monitoring of circulating tumor DNA can predict chemotherapy response and prognosis in metastatic triple-negative breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-27.

The cellulose fibers functionalized with star-like zinc oxide nanoparticles with boosted antibacterial performance for hygienic products

Bacterial infectious diseases are serious health problem which extends to economic and social complications. Moreover, bacterial antibiotic resistance, lack of suitable vaccine or emergence of new mutations is forcing the development of novel antimicrobial agents. The objective of this study is to synthesize and characterize star-like zinc oxide nanoparticles for the application of antibacterial activities in cellulose based hygiene products. ZnO NPs were in situ synthesized via precipitation method on the surface of cellulose fibers. Since bactericidal activity of nanoparticles in part depends on the concentration in the growth medium, various amount of ZnO was incorporated into cellulose matrix ranging from 1 to 3 wt%. Microscopic (TEM, SEM) and spectroscopic (FT-IR, XRD) methods were utilized to investigate the final products. The infrared absorption spectra analysis supported by theoretical finding that during the reaction, ZnO nanoparticles could be bonded with cellulose fibers via hydrogen bonding. The yield of functionalization was determined through thermogravimetric analysis. Collected data proved the successful functionalization of the cellulose fibers with nanoparticles. Static contact angle measurements were carried out showing absorptive character of as prepared fabrics. All the samples were tested for the antibacterial properties and the results were compared to the samples prepared from the pristine cellulose fibers. Moreover, mechanical tests were performed revealing that the addition of only 2 wt% of the nanofiller boosted tensile, tearing and bursting strength by a factor of 1.6, 1.4 and 2.2 in comparison to unfunctionalized paper sample, respectively. Fabricated fabric presenting high hydrophilicity and antibacterial properties have gained increased applications in fabric industry, including hygiene product industry and hence the result of this study would be a welcomed option.