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1.
Zhongguo Bingdubing Zazhi = Chinese Journal of Viral Diseases ; - (4):284, 2022.
Article in English | ProQuest Central | ID: covidwho-2040496

ABSTRACT

Objective To understand the genomic characteristics of SARS-CoV-2 from 40 imported cases with confirmed COVID-19 in Sichuan during January and March 2022. Methods Total viral RNA was extracted from respiratory samples of 182 confirmed COVID-19 cases who entered China through Chendu International Airport from January to March 2022.Mutation nucleic acid detection kit was used to identify the mutant strains and Illumina sequencing platform was applied for whole genome sequence(WGS) of virus.SARS-CoV-2 reference sequences were downloaded from NCBI database for genetic evolution and antigen variation analysis.The Nextclade and Pangolin online virus analysis platform were used to determine the virus family and type,and to analyze the mutation loci of the virus.The phylogenetic tree was constructed,along with the epidemiological data of cases to analyze the source and correlation of viruses. Results Among 182 imported COVID-19 cases,B.1.617.2 mutations were identified in 3 cases and B.1.1.529 mutations were detected in 57 cases.A total of 40 SARS-CoV-2 whole genome sequences with coverage>95% were obtained in this study.Nextclade typing analysis showed that 3 sequences belonged to 21J(Delta),5 sequences belonged to 21K(Omicron)and the remaining 32 sequences belonged to 21L(Omicron).Pangolin typing analysis showed that the 3 sequences of 21J(Delta)belonged to AY.4,AY.109and B.1.617.2,the 5sequences of 21K(Omicron)all belonged to BA.1.1,and the remaining 32 sequences of 21L(Omicron)belonged to BA.2.Our sequence results were99.7% consistency with the Omicron variants sequences in current GISAID database.Compared with the reference sequence strain Wuhan-Hu-1(NC_045512.2),45,47and 42nucleotide variation sites and 36,25 and 36amino acid variation sites were found in the 3 sequences of 21J(Delta).There were average 59(26-64)nucleotide mutation sites and 48(10-53)amino acid mutation sites in the 5sequences of 21K(Omicron).The median number of nucleotide mutation sites of 71(66-76)and amino acid mutation sites of 53(40-56)were identified in the 32sequences of 21L(Omicron).Phylogenetic tree analysis showed that 40SARS-CoV-2WGSs were all related to the current variants of concern(VOC). Conclusions Continuous sequencing of SARS-CoV-2whole genome from imported cases with confirmed COVID-19is of great significance for the prevention and control of the outbreak and prevalence of local epidemic caused by imported viruses in Sichuan.

2.
Viruses ; 14(8):16, 2022.
Article in English | MEDLINE | ID: covidwho-2039975

ABSTRACT

The on-going global pandemic of COVID-19 is caused by SARS-CoV-2, which features a proofreading mechanism to facilitate the replication of its large RNA genome. The 3'-to-5' exoribonuclease (ExoN) activity of SARS-CoV-2 non-structural protein 14 (nsp14) removes nucleotides misincorporated during RNA synthesis by the low-fidelity viral RNA-dependent RNA polymerase (RdRp) and thereby compromises the efficacy of antiviral nucleoside/nucleotide analogues. Here we show biochemically that SARS-CoV-2 nsp14 can excise the natural antiviral chain-terminating nucleotide, 3'-deoxy-3',4'-didehydro-cytidine 5'-monophosphate (ddhCMP), incorporated by RdRp at the 3' end of an RNA strand. Nsp14 ExoN processes an RNA strand terminated with ddhCMP more efficiently than that with a non-physiological chain terminator 3'-deoxy-cytidine monophosphate (3'-dCMP), whereas RdRp is more susceptible to chain termination by 3'-dCTP than ddhCTP. These results suggest that nsp14 ExoN could play a role in protecting SARS-CoV-2 from ddhCTP, which is produced as part of the innate immune response against viral infections, and that the SARS-CoV-2 enzymes may have adapted to minimize the antiviral effect of ddhCTP.

3.
International Journal of Molecular Sciences ; 23(18):10686, 2022.
Article in English | ProQuest Central | ID: covidwho-2039870

ABSTRACT

Body fluid identification at crime scenes can be crucial in retrieving the appropriate evidence that leads to the perpetrator and, in some cases, the victim. For this purpose, immunochromatographic tests are simple, fast and suitable for crime scenes. The potential sample is retrieved with a swab, normally a cotton swab, moistened in a specific buffer. Nonetheless, there are other swab types available, which have been proven to be efficient for DNA isolation and analysis. The aim of this study is to evaluate the efficiency of different swab types for body fluid identification as well as DNA isolation and characterization. Fifty microliters of human saliva were deposited in three different types of fabric (denim, cotton, and polyester). After 24 h at room temperature, samples were recovered by applying three different swab types, and the tests were performed. Subsequently, total DNA was recovered from the sample buffer. Cotton swabs performed worse in denim and cotton fabrics in both immunochromatography tests and DNA yield. No differences were observed for polyester. In contrast, and except for two replicates, it was possible to obtain a full DNA profile per fabric and swab type, and to identify the mtDNA haplogroup. In this paper, the impact of swab types on body fluid identification through the application of immunochromatographic tests is analyzed for the first time. This work corroborates previous research related to the influence of swab types in nuclear DNA isolation and characterization.

4.
International Journal of Molecular Sciences ; 23(18):10347, 2022.
Article in English | ProQuest Central | ID: covidwho-2039864

ABSTRACT

This review outlines the role of electrostatics in computational molecular biophysics and its implication in altering wild-type characteristics of biological macromolecules, and thus the contribution of electrostatics to disease mechanisms. The work is not intended to review existing computational approaches or to propose further developments. Instead, it summarizes the outcomes of relevant studies and provides a generalized classification of major mechanisms that involve electrostatic effects in both wild-type and mutant biological macromolecules. It emphasizes the complex role of electrostatics in molecular biophysics, such that the long range of electrostatic interactions causes them to dominate all other forces at distances larger than several Angstroms, while at the same time, the alteration of short-range wild-type electrostatic pairwise interactions can have pronounced effects as well. Because of this dual nature of electrostatic interactions, being dominant at long-range and being very specific at short-range, their implications for wild-type structure and function are quite pronounced. Therefore, any disruption of the complex electrostatic network of interactions may abolish wild-type functionality and could be the dominant factor contributing to pathogenicity. However, we also outline that due to the plasticity of biological macromolecules, the effect of amino acid mutation may be reduced, and thus a charge deletion or insertion may not necessarily be deleterious.

5.
BMC Proc ; 16(Suppl 5):5, 2022.
Article in English | ProQuest Central | ID: covidwho-2038752

ABSTRACT

Targeting mutant p53 for the treatment of triple negative breast cancer: a pre-clinical study Anna Lawless1, Shane O’Grady2, Minhong Tang2, Michael J. Duffy2,3 1UCD School of Medicine, University College Dublin, Belfield, Dublin, Ireland;2UCD School of Medicine, Conway Institute of Biomedical and Biomolecular Research, University College Dublin, Belfield, Dublin, Ireland;3UCD Clinical Research Centre, St. Vincent’s University Hospital, Dublin, Ireland Correspondence: Anna Lawless (anna.lawless@ucdconnect.ie) Triple negative breast cancer (TNBC) refers to an invasive subset of breast cancer that lacks oestrogen receptors (ER), progesterone receptors (PR) and lacks amplification of HER2 [1]. [...]these patients cannot be treated with a targeted therapy and have poorer outcomes compared to patients with other subforms of breast cancer. p53 it is the most frequently mutated gene in human cancer. For all cell lines investigated, ATO induced significant levels of apoptosis at a concentration of 5 μM. Although our data are preliminary, we conclude that ATO is a potential new therapy for the treatment of p53 mutated cancer, including triple negative breast cancer. Since ATO is already approved for the treatment of acute promyelocytic leukaemia (APL), it should be straightforward to repurpose it for TNBC. Katie Ryan1, Emma-Louise Rogers2, John Cronin2, Conor Prendergast2 1School of Medicine, University College Dublin, Dublin, Ireland;2Department of Emergency Medicine, St. Vincent’s University Hospital, Dublin 4, Ireland Background Emergency Medicine (EM) clinicians are required to make critical decisions, often with limited information, resources, and time. Microfluidic-microwave platforms for real-time, non-invasive and sensitive monitoring of bacteria and antibiotic susceptibility testing Rakesh Narang1,2,3, Sevda Mohammadhi4, Mehdi Mohammadi Ashani1,2, Mohammad Zarifi4, Amir Sanati-Nezhad1,2,3 1BioMEMS and Bioinspired Microfluidic Laboratory, Department of Mechanical and Manufacturing Engineering, University of Calgary, Calgary, Alberta, Canada, 2Center for BioEngineering Research and Education, University of Calgary, Calgary, Alberta, Canada, 3Biomedical Engineering Graduate Program, University of Calgary, Calgary, Alberta, Canada, 4Okanagan Microelectronics and Gigahertz Applications (OMEGA) Lab, Faculty of Applied Science, Kelowna, BC, Canada Correspondence: Rakesh Narang (rakesh.narang@ucdconnect.ie) In 2019, the CDC reported over 2.8 million antibiotic-resistant bacterial infections in the United States [1].

6.
Computational Intelligence and Neuroscience : CIN ; 2022, 2022.
Article in English | ProQuest Central | ID: covidwho-2038380

ABSTRACT

An area of medical science, that is, gaining prominence, is DNA sequencing. Genetic mutations responsible for the disease have been detected using DNA sequencing. The research is focusing on pattern identification methodologies for dealing with DNA-sequencing problems relating to various applications. A few examples of such problems are alignment and assembly of short reads from next generation sequencing (NGS), comparing DNA sequences, and determining the frequency of a pattern in a sequence. The approximate matching of DNA sequences is also well suited for many applications equivalent to the exact matching of the sequence since the DNA sequences are often subject to mutation. Consequently, recognizing pattern similarity becomes necessary. Furthermore, it can also be used in virtually every application that calls for pattern matching, for example, spell-checking, spam filtering, and search engines. According to the traditional approach, finding a similar pattern in the case where the sequence length is ls and the pattern length is lp occurs in O (ls∗lp). This heavy processing is caused by comparing every character of the sequence repeatedly with the pattern. The research intended to reduce the time complexity of the pattern matching by introducing an approach named “optimized pattern similarity identification” (OPSI). This methodology constructs a table, entitled “shift beyond for avoiding redundant comparison” (SBARC), to bypass the characters in the texts that are already compared with the pattern. The table pertains to the information about the character distance to be skipped in the matching. OPSI discovers at most spots of similar patterns occur in the sequence (by ignoring è mismatches). The experiment resulted in the time complexity identified as O (ls. è). In comparison to the size of the pattern, the allowed number of mismatches will be much smaller. Aspects such as scalability, generalizability, and performance of the OPSI algorithm are discussed. In comparison with the hamming distance-based approximate pattern matching algorithm, the proposed algorithm is found to be 69% more efficient.

7.
Int Immunopharmacol ; 111: 109128, 2022 Aug 08.
Article in English | MEDLINE | ID: covidwho-2036144

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), responsible for the outbreak of coronavirus disease 2019 (COVID-19), has shown a vast range of clinical manifestations from asymptomatic to life-threatening symptoms. To figure out the cause of this heterogeneity, studies demonstrated the trace of genetic diversities whether in the hosts or the virus itself. With this regard, this review provides a comprehensive overview of how host genetic such as those related to the entry of the virus, the immune-related genes, gender-related genes, disease-related genes, and also host epigenetic could influence the severity of COVID-19. Besides, the mutations in the genome of SARS-CoV-2 __leading to emerging of new variants__ per se affect the affinity of the virus to the host cells and enhance the immune escape capacity. The current review discusses these variants and also the latest data about vaccination effectiveness facing the most important variants.

8.
Front Vet Sci ; 9: 931272, 2022.
Article in English | MEDLINE | ID: covidwho-2032824

ABSTRACT

New variants of infectious bronchitis viruses (IBVs; Coronaviridae) continuously emerge despite routine vaccinations. Here, we report genome sequence variations of IBVs identified by random non-targeted next generation sequencing (NGS) of vaccine and field samples collected on FTA cards from commercial flocks in Mexico in 2019-2021. Paired-ended sequencing libraries prepared from rRNA-depleted RNAs were sequenced using Illumina MiSeq. IBV RNA was detected in 60.07% (n = 167) of the analyzed samples, from which 33 complete genome sequences were de novo assembled. The genomes are organized as 5'UTR-[Rep1a-Rep1b-S-3a-3b-E-M-4b-4c-5a-5b-N-6b]-3'UTR, except in eight sequences lacking non-structural protein genes (accessory genes) 4b, 4c, and 6b. Seventeen sequences have auxiliary S2' cleavage site located 153 residues downstream the canonically conserved primary furin-specific S1/S2 cleavage site. The sequences distinctly cluster into lineages GI-1 (Mass-type; n = 8), GI-3 (Holte/Iowa-97; n = 2), GI-9 (Arkansas-like; n = 8), GI-13 (793B; n = 14), and GI-17 (California variant; CAV; n = 1), with regional distribution in Mexico; this is the first report of the presence of 793B- and CAV-like strains in the country. Various point mutations, substitutions, insertions and deletions are present in the S1 hypervariable regions (HVRs I-III) across all 5 lineages, including in residues 38, 43, 56, 63, 66, and 69 that are critical in viral attachment to respiratory tract tissues. Nine intra-/inter-lineage recombination events are present in the S proteins of three Mass-type sequences, two each of Holte/Iowa-97 and Ark-like sequence, and one each of 793B-like and CAV-like sequences. This study demonstrates the feasibility of FTA cards as an attractive, adoptable low-cost sampling option for untargeted discovery of avian viral agents in field-collected clinical samples. Collectively, our data points to co-circulation of multiple distinct IBVs in Mexican commercial flocks, underscoring the need for active surveillance and a review of IBV vaccines currently used in Mexico and the larger Latin America region.

9.
GERMS ; 12(2):298-303, 2022.
Article in English | EMBASE | ID: covidwho-2033515

ABSTRACT

Introduction COVID-19 is an emerging infectious disease that remains to be further investigated. Case report Here, we describe a case of COVID-19 in an octogenarian woman with comorbidities who slowly recovered during hospitalization, but died due to sudden cardiac death after 2 weeks of hospitalization. Her nasopharyngeal and anal swabs returned positive for SARS-CoV-2 by RT-PCR on day 7 of hospitalization. The NGS showed possible intraindividual evolution of virus. The sample from the nasopharyngeal swab yielded a B.1470 variant classified as clade GH. This variant showed mutation in the spike gene D614G;N gene;NS3 gene;NSP2 gene and NSP12 gene. The sample from the anal swab showed similar mutation but with additional point mutation in spike gene S12F and was classified as B.1.465 variant. Conclusions The possibility of the gastrointestinal tract that served as reservoir for virus mutation accumulation should also be considered and the potential impact of viral fecal transmission in the environment should be further investigated.

10.
HemaSphere ; 6:1985-1987, 2022.
Article in English | EMBASE | ID: covidwho-2032163

ABSTRACT

Background: Ibrutinib (IBR) is an oral covalent Bruton tyrosine kinase inhibitor (BTKi), licensed for treatment of relapsed or refractory mantle cell lymphoma (MCL). Under NHS interim Covid-19 agreements in England, IBR with or without rituximab (R) was approved for the frontline treatment for MCL patients (pts) as a safer alternative to conventional immunochemotherapy. Although recent phase 2 studies have reported high response rates in low-risk patients for this combination in the frontline setting, randomised phase 3 and real-world data are currently lacking. Aims: To describe the real-world response rates (overall response rate (ORR), complete response (CR) rate) and toxicity profile of IBR +/-R in adult patients with previously untreated MCL. Methods: Following institutional approval, adults commencing IBR +/-R for untreated MCL under interim Covid-19 arrangements were prospectively identified by contributing centres. Hospital records were interrogated for demographic, pathology, response, toxicity and survival data. ORR/CR were assessed per local investigator according to the Lugano criteria using CT and/or PET-CT. Results: Data were available for 66 pts (72.7% male, median age 71 years, range 41-89). Baseline demographic and clinical features are summarised in Table 1. 23/66 pts (34.8%) had high-risk disease (defined as presence of TP53 mutation/deletion, blastoid or pleomorphic variant MCL, or Ki67%/MiB-1 ≥30%). IBR starting dose was 560mg in 56/62 pts (90%) and was given with R in 22/64 pts (34%). At a median follow up of 8.7 months (m) (range 0-18.6), pts had received a median of 7 cycles of IBR. 19/60 pts (32%) required a dose reduction or delay in IBR treatment. New atrial fibrillation and grade ≥3 any-cause toxicity occurred in 3/59 pts (5.8%) and 8/57 (14.0%) respectively. For the whole population and high-risk pts only, ORR was 74.4% and 64.7% respectively (p=0.2379), with a median time to response of 3.8m, coinciding with the first response assessment scan. Seven pts (16.7%), of whom 2 had highrisk disease, attained CR at a median of 6.0m. ORR for pts receiving vs not receiving R were 84.2% and 66.7% respectively (p=0.1904). IBR was discontinued in 20/61 pts (32.8%) at a median time to discontinuation of 4.1m, due to progressive disease (PD, 19.7%), toxicity (4.9%), death (3.3%;1 pt each of Covid-19 and E. coli infection), pt choice (3.3%) and other unspecified reasons (1.6%). 15/66 pts (22.7%) overall and 7/23 (30.4%) with high-risk disease progressed on IBR at a median time to PD of 4.0m. No pts underwent autologous stem cell transplantation consolidation during the study period. 12/57 pts (21.1%) received second line treatment (R-chemotherapy n=7, Nordic MCL protocol n=2, VR-CAP n=2, pirtobrutinib n=1). Response to second line treatment was CR in 4/11 pts, PD in 7/11. Of the 2 Nordic-treated patients, 1 had CR after cycle 2 and 1 PD. Fourteen pts (21.2%) died during the follow up period, due to MCL (n=11), Covid-19 (n=2) and congestive cardiac failure (n=1). Overall survival was lower for patients with high-risk disease (HR 0.55, p=0.038). Image: Summary/Conclusion: In this real-world UK cohort of pts receiving first-line IBR +/-R for MCL, including older and high-risk pts, we report high ORR rates in a similar range to the phase II Geltamo IMCL-2015 study of combination IBR-R in an exclusively low-risk population. Documented CR rates were lower, possibly reflecting a low usage of rituximab in the Covid-19 pandemic as well as CT assessment of response. Treatment was generally well tolerated, with low rates of toxicityrelated treatment discontinuation. The study is ongoing.

11.
HemaSphere ; 6:1104-1105, 2022.
Article in English | EMBASE | ID: covidwho-2032162

ABSTRACT

Background: The introduction of venetoclax into clinical practice has improved the outcome of patients with relapsed/refractory chronic lymphocytic leukemia (RR-CLL). The results of the MURANO trial published in March 2018 showed significantly longer progression-free survival (PFS) and overall survival (OS) in RR-CLL patients treated with venetoclax and rituximab (VEN-R) comparing to bendamustine and rituximab (BR) and resulted in the approval of VEN-R in the therapy of RR-CLL in the European Union and the United States. It should be noted that the results of registration studies often do not correspond with the data from real-life observations. Aims: To study the clinical efficacy and safety profile of VEN-R treatment in RR-CLL patients outside clinical trials. Methods: We performed retrospective analysis of RR-CLL patients treated with VEN-R in hematology centers of the Polish Adult Leukemia Study Group (PALG) from 2019 to 2021. Results: Clinical data of 117 RR-CLL patients treated with VEN-R were collected. Median patient age upon initiation of VEN-R therapy was 67 years (range 33 - 84 years). Seventy-two patients (61.5%) were men. Median Cumulative Illness Rating Scale (CIRS) was 6 (range 2 -16). Patients were treated with a median of 2 (range 1-9) previous lines of therapy, whereas 32 patients (27.4%) had relapsed following the first line of treatment. Overall, 25 patients (21.4%) had 17p deletion, whereas TP53 mutation was identified in 13 patients (11.1%). The median follow-up was 9.96 months (range 0.27 -29.13). The overall response rate (ORR) was 95.2%. Seventeen patients (14.5%) achieved complete remission (CR), 83 (70.9%) partial remission (PR), while in 5 patients (4.3%) disease progression was noted. In the patients with 17p deletion (n=22) or TP53 mutation (n=11), CR and PR were observed in 4 (12.1%) and 29 (87.9%) patients, respectively. The median PFS in the whole cohort was 20.8 (95% CI 18.43 -not reached) months and the median OS was not reached. In our study none of the analyzed clinico-pathological factors had significant impact on ORR, PFS and OS. During the follow-up time four (3.4%) cases of Richter transformation were diagnosed. There were 18 deaths recorded during the course of observation;3 (16.7%) due to disease progression and 7 (38.9%) due to COVID-19 infection. The others were due to infections other than SARS-CoV-2 (n=3, 16.7%) and the cause of death could not be specified in five cases (27.8%). Eighty-three patients (70.9%) remain on treatment, while treatment was discontinued in thirty-four cases (29.1%). Reasons for therapy discontinuation included patient's death (52.9%), treatment-related cytopenias (17.6%), disease progression (14.7%), Richter's transformation (11.8%), autoimmune hemolytic anemia (5.9%), diarrhea (2.9%) and infections (8.8%). In one case treatment discontinuation was due to consent withdrawal and one patient was lost to follow-up. The following adverse events of VEN-R treatment were reported during the study: all grade neutropenia (71.8% with grade 3/4 in 55.6%), anemia (51.3%), thrombocytopenia (47%), pneumonia (9.4%), neutropenic fever (6.8%), autoimmune hemolytic anemia (4.3%), immune thrombocytopenic purpura (1.7%), diarrhea (4.3%) and in one case exacerbation of heart failure was observed. Summary/Conclusion: In this retrospective analysis the outcomes of treatment with the VEN-R regimen in real-life setting were worse than those reported in the MURANO trial.

12.
HemaSphere ; 6:2386-2387, 2022.
Article in English | EMBASE | ID: covidwho-2032147

ABSTRACT

Background: Gemtuzumab ozogamicin (GO), an anti-CD33 immunoconjugate Antibody is currently approved in combination with 7 + 3 in low- and intermediate risk acute myeloid leukaemia (AML). These patients are candidate for consolidation with autologous stem cell transplantation (ASCT) particularly when MRD- is obtained. GO can improve the rate of MRD negativity. There are limited data on the effect of its addition on the mobilization of Hemopoietic Stem Cells (HSC). Aims: To assess the feasibility of mobilization of HSC after re-introduction into market of GO at 3mg/m2 in 2019. Methods: We retrospectively studied AML patients undergoing 3+7 + GO induction and Ara-C + Daunorubicine + GO, consolidation (doses are derived from label instructions and ALFA0701 study) and mobilization on day +20 using GCSF 10μg/kg. CD34+ were monitored, and patients were harvested when a threshold of 20 cells/μL was reached in peripheral blood. Results: In 2020 and 2021, also considering constrains caused by COVID-19 pandemics, we attempted mobilization in our 3 Italian centres of 14 patients with a diagnosis of CD33+ de novo-AML. The median age was 52 years (range 29-65 yrs.), 4 were males and 10 females;11 patients carried a mutation of NPM1 and all had a normal karyotype except one with t(10p12;11q14) (Table 1). All received 3+7+GO induction and achieved a CR. Therefore, we started consolidation (total ARA-C 8g/m2) + GO as inpatient. Ten patients (71%) reached the established threshold of 20 CD34+ /μL and were successfully harvested, while 4 patients (29%) failed mobilization. The median day of apheresis was D+26 from the start to chemotherapy (range 22- 39). The median number of circulating CD34+ cells on the day of collection was 35.9 cells/μL (range 20-2153 cells/μL). The median CD34+ harvested was 4.65 x 106/kg (range 1.8- 44.6 x 106/kg). In our cohort, 4 patients (28% of the entire cohort and 40% of the harvested patients) underwent ASCT, 3 achieved favourable engraftment, while in the last patient ASCT is ongoing. Several reasons prevented ASCT in the remaining 6 patients: 3 patients underwent allogeneic SCT (2 had positive MRD on harvested apheresis;1 was reclassified as high-risk ELN2017 due to RUNX1 mutation resulting from NGS panel), 2 refused ASCT and one suffered early relapse. Summary/Conclusion: In our patients, the addition of GO did not impair HSC mobilization and harvesting that was reached in about 71% of cases, similarly to the AML-10 trial of the EORTC and GIMEMA Leukemia Groups where 70% of patients were successfully harvested. Our data are particularly interesting because in the pivotal ALFA0701 study, only one patient underwent Autologous- SCT, but in the control arm. An important limit of our case-series is that only 4 patients were auto-transplanted, so we have scant data on engraftment. In particular, evaluating day to engraftment of platelets would be interesting, given the known increase of thrombocytopaenia in patients treated with GO. In conclusion, mobilization with GO is feasible and further studies are warranted to evaluate the effects of fractioned doses of GO on HSC mobilization and ASCT outcome;the ongoing trial GIMEMA AML1819 - EudraCT number 2019-003871-20 - will prospectively assess the effect of GO, but with lower doses of ARA-C (total ARA-C 6 g/m2). (Table Presented).

13.
HemaSphere ; 6:2303, 2022.
Article in English | EMBASE | ID: covidwho-2032146

ABSTRACT

Background: Nucleoside analog (NAs) drugs are used for the treatment of a variety of diseases, such as cancers and viral infections. After phosphorylation of viral and host kinases, NA drugs compete with the corresponding naturally occurring nucleotide during DNA replication of the infected cell. After incorporation, they can lead to mutations, or chain termination. However, because of their mechanism of action, NA are also potentially mutagenic to the genome of physiologically normal cells. Indeed, we have shown that treatment with the antiviral NA ganciclovir (GCV) after stem cell transplantation induces an increased mutation burden in the hematopoietic stem and progenitor cells (HSPCs) of pediatric leukemia patients. Using mutational signature analysis, we provided evidence that GCV-induced mutagenesis contributes to development of relapses and second malignancies in pediatric patients by inducing driver mutations. Over 30 NA drugs have been approved for clinical use and millions of people receive antiviral treatment worldwide to treat viral infections, including COVID-19. However, the mutagenicity in normal cells and potential carcinogenicity is unclear. Aims: Here, we aimed to systematically assess the mutational consequences of antiviral NAs in human HSPCs and identify underlying mechanisms. Methods: By combining in vitro treatment of umbilical cord blood-derived HSPCs with whole-genome sequencing (WGS) analyses, we provide a compendium of mutational consequences of antiviral NAs in a relevant human tissue (i.e., toxicity to the hematopoietic system is often dose-limiting). We treated HSPCs with IC40-60 concentration of the assessed compound followed by clonal expansions to obtain sufficient DNA for WGS. Using established bioinformatic pipelines, we catalogued the somatic mutations and mutational signatures in these cells. Results: At time of writing, 5 out of 7 tested antiviral NAs induce an enhanced mutation burden in exposed HSPCs. For some of this antiviral NAs we were able to identify unique unreported mutational signatures. Of note, the thymidine analog brivudine showed the highest increase in single base substitutions, which were characterized by a T>C signature, depleted for flanking cytosines. Furthermore, like GCV, we also observed a signature characterized by C>ApA substitution after treatment with the penciclovir, a molecule nearly identical to GCV. Currently we are working on machine learning approach to identify relevant mutation characteristics and modes of action as well as to screen cancer genome databases for mutational signature occurrence. Summary/Conclusion: Many compounds of the NA class currently prescribed for the treatment of viral infections are mutagenic to healthy cells. This calls for more thorough screening of these drugs, incorporation of information on mutagenicity to healthy cells in drug safety guidelines and patient surveillance over time.

14.
HemaSphere ; 6:861-862, 2022.
Article in English | EMBASE | ID: covidwho-2032127

ABSTRACT

Background: Venetoclax (Ven) in combination with hypomethylating agents, such as azacitidine (Aza) and low dose cytarabine (LDAC) has been shown to be effective therapy in acute myeloid leukaemia (AML) and has become standard of care for newly-diagnosed patients unfit for intensive chemotherapy (DiNardo et al., 2020;Wei et al., 2019;Pollyea et al., 2020). Efficacy has also been shown in the relapsed/refractory (R/R) setting in more limited data sets (Báez-Gutiérrez et al., 2021;Pollyea et al., 2020, Stahl et al., 2020;DiNardo et al., 2019). Ven combination therapy has become widely used in newly-diagnosed patients in the UK since its approval during the COVID-19 pandemic as an alternative to intensive chemotherapy and subsequently for patients unfit for intensive therapy. Aims: We describe the characteristics and outcomes of patients with AML or high risk myelodysplastic syndrome (HRMDS) receiving Ven combinations in frontline and R/R settings to provide real-world insight into their use in UK clinical practice. Methods: A retrospective analysis was performed of all patients with AML or HR-MDS who received Ven combination therapy at University College London Hospital between April 2020 and September 2021. Patient demographics, treatment history and bone marrow results were obtained from electronic health care and laboratory records. Disease stratification and response assessments were made as per European LeukemiaNet (ELN) criteria (Döhner et al., 2017). Results: At the time of analysis, 95 patients received Ven combinations (61 as frontline treatment and 34 for R/R AML), with a median follow up of 14 months. The majority of patients in both groups had adverse risk ELN classification (70.5% of frontline patients, 64.7% of R/R) and received Ven-Aza (100% frontline and 91.1% R/R) (Table 1). The median ages were 72 and 59 years respectively. The incidence of composite CR/CRi was 70.5% in the frontline setting, with median duration of response (DoR) of 8.3 months and overall survival (OS) of 7.1 months. In R/R AML, the CR/CRi rate was 64.7%, median DoR 10.5 months and median OS 9.8 months. Four out of the 43 patients who achieved CR/CRi (9.3%) following frontline treatment and 9 of the 22 R/R (40.9%) patients proceeded to allogeneic stem cell transplant (alloSCT) post induction. The median survival for all patients who underwent alloSCT is not reached in this analysis. The highest CR/CRi rates were observed in intermediate risk patients (90.9% in frontline treatment, 71.4% in R/R), with lower rates in both favourable (80% and 66.7%) and adverse risk patients (65.1% and 59.1% respectively). The presence of NPM1 and IDH1/2 mutations were associated with high CR/CRi rates in both the frontline (85.7% and 84.6% respectively) and R/R groups (100% and 81.8%), with below average response rates seen in TP53 mutated AML (62% in frontline, 40% in R/R). Notable responses were seen in patients with RUNX1 mutations in both settings (77.8% frontline, 66.6% R/R). Summary/Conclusion: Our data describes real world effectiveness for venetoclax combinations as both frontline and salvage therapy in UK clinical practice, similar to that seen in clinical trials. This further contributes to our understanding of these therapies, in particular their use as a viable treatment option in R/R patients and as a bridge to alloSCT, and highlights the importance of further characterisation of genetic predictors of response to inform treatment decisions in real-world practice.

15.
HemaSphere ; 6:1149-1150, 2022.
Article in English | EMBASE | ID: covidwho-2032119

ABSTRACT

Background: In pts with CML, the BCR::ABL1 T315I mutation is associated with poor clinical outcomes and confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs). Until recently, ponatinib (PON) was the only TKI available for these pts, but its use may be limited by associated cardiovascular events. In the primary analysis of the phase I trial X2101, asciminib-the 1st BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP)-demonstrated efficacy and a favorable safety profile in heavily pretreated pts with CML with T315I. These results supported the FDA approval of asciminib as a new treatment option for pts with CML-CP with T315I (NCCN 2021). We report updated efficacy and safety data in these pts (data cutoff: January 6, 2021). Aims: Provide updated safety and efficacy data for pts with CML-CP with T315I treated with asciminib monotherapy 200 mg twice daily (BID) after added exposure. Methods: Pts with CML-CP with T315I were enrolled if treated with ≥1 prior TKI and no other effective therapy was available, provided informed consent, and received asciminib 200 mg BID. Results: 48 pts with T315I were included;2 (4.2%) pts had additional BCR::ABL1 mutations at baseline. Eight (16.7%), 15 (31.3%) and 25 (52.1%) pts received 1,2, and ≥3 prior TKIs, respectively. At data cutoff, treatment was ongoing in more than half (27 [56.3%]) of pts;the predominant reason for treatment discontinuation was physician's decision (11 [22.9%]), mainly due to lack of efficacy. Of the 48 pts, 45 were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR);3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable pts, 19 (42.2%) achieved MMR by wk 24 and 22 (48.9%) by wk 96;19 were still in MMR at the cutoff date. Evaluable pts included 26 PON-pretreated and 19 PONnaive pts;34.6% and 68.4%, respectively, achieved MMR by the cutoff date (Table). The probability of pts maintaining MMR for ≥96 wks was 84% (95% CI, 68.1-100.0). Thirteen (28.9%) and 11 (24.4%) pts achieved MR4 and MR4.5, respectively. Twenty (54.1%) and 23 (62.2%) of 37 pts with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS ≤1% by wk 48 and 96, respectively. The median duration of exposure was 2.08 (range, 0.04-4.13) yrs with more than half (27 [56.3%]) of pts receiving treatment for ≥96 wks;the median daily dose intensity was 398.3 (range, 179-400) mg/day. The safety/tolerability profile of asciminib remained favorable after ≈9 months of added follow-up (Table). The most common (≥5%) grade ≥3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations), thrombocytopenia (14.6%), and vomiting, ALT increase, abdominal pain, hypertension, anemia, neutropenia, and neutrophil count decrease (6.3% each). Arterial occlusive events occurred in 4 (8.3%) pts;none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation were reported in 2 new pts since the previous data cutoff;both pts discontinued and died due to COVID-19. These were the only study deaths reported in this pt population. Image: Summary/Conclusion: Asciminib monotherapy 200 mg BID exhibited a sustained, favorable safety profile after added exposure with no new safety signals in pts with CML-CP with T315I-a population with high unmet medical need. The clinical efficacy of asciminib is demonstrated by the high proportion of pts achieving durable MMR and BCR::ABL1IS ≤ 1%. The updated analysis confirms asciminib as a treatment option for pts with CML-CP with T315I, including those for whom treatment with PON has failed.

16.
HemaSphere ; 6:3284-3285, 2022.
Article in English | EMBASE | ID: covidwho-2032098

ABSTRACT

Background: The Bruton's tyrosine kinase (BTK) inhibitor acalabrutinib is approved for treatment of chronic lymphocytic leukemia(CLL). Acalabrutinib induces durable remissions in most CLL patients, which mostly are partial remissions (PR), and therefore treatment typically is given as long-term monotherapy. As a potential alternative we developed a time-limited regimen, combining acalabrutinib with obinutuzumab. Aims: Here, we report early results from 14 treatment-naïve patients with CLL who enrolled in this ongoing phase 2 trial (NCT04505254) since September, 2020 at MD Anderson Cancer Center. Methods: Patients and Study Design: Treatment-naïve CLL patients requiring therapy as per iwCLL criteria receive acalabrutinib 100 mg orally twice a day for 24 cycles, combined with monthly obinotuzumab for 6 doses, starting in cycle 3. The first dose of obinutuzumab is divided into 100 mg on day 1 and 900 mg on day 2 of cycle 3;1000 mg are given during subsequent cycles (cycles 4-8). Patients who do not achieve a complete remission (CR) after cycle 8 can receive an additional 6 monthly doses of obinotuzumab during cycles 9 -14. Treatment is discontinued after 24 cycles, and patients will be monitored. The primary objective is to determine the durability of remissions after treatment discontinuation, secondary objectives are to determine clinical and laboratory characteristics that predict for early versus late relapse after time-limited therapy. Results: The median age of the patients is 70 yrs (range, 40 -83 yrs), 14% had del17p or TP53 mutation, 43% had an unmutated IgHV and 71% advance stage disease (RAI stage III and IV). The median baseline absolute lymphocyte count (ALC) and b2 microglobulin at start of therapy were 39.2x109/L (range: 7.1 - 188.4 x 109/L) and 4.2 mg/L (range: 2.2 - 7.9 mg/L), respectively. After a median follow-up of 7 months (2 - 16 months), 13 (93%) of patients remain on study;one patient died (7%) due from complications from a presumed bacterial (COVID19-negative) pneumonia after 2 months on therapy. The estimated one-year PFS and OS for the cohort is 92.8 %. Seven patients were evaluable for response assessment after 8 months of therapy. No patient has yet discontinued therapy. All patients achieved a PR (one patient with undetectable minimal residual disease/U-MRD in the bone marrow), accounting for an overall responsonse rate of 100%. The median levels of bone marrow infiltration by CLL cells, quantified by flow cytometry, declined from 83.6% (range: 54.3 - 94.0 %) at baseline to 4.1% (range, 0.0 - 63.3%, n=7, p<0.05, see figure) after 6 cycles of combination treatment. Sixty-four percent of patients completed all doses of obinotuzumab, 50% requiered a dose reduction of acalabrutinib to 100 mg per day due to adverse events (AE). Grade 33 AE were observed in 4 patients (29%), which included decreased neutrophil counts (n=2), syncope (n=1), and grade 5 lung infection (COVID19 not detected, n=1). The most frequently reported non-serious related AE (3 2 patients) were anemia (n=5 [36%]), decreased platelets counts (n=3 [21%]), bruising (n=3 [21%]), limbs edema (n=2 [15%]) and headache (n=2 [15%]). All these events were grade 1. Importantly, no bleeding or atrial fibrillation events were observed. 3285 (Figure Presented ) Summary/Conclusion: Our preliminary data indicate that combination therapy of acalabrutinib plus obinotuzumab induces remissions with a major reduction in bone marrow disease after 6 months of combination therapy. Longer treatment and follow-up is warranted to determine the durability of responses after therapy discontinuation.

17.
Journal of Thoracic Oncology ; 17(9):S508-S509, 2022.
Article in English | EMBASE | ID: covidwho-2031530

ABSTRACT

Introduction: Lung cancer symptoms and secondary effects of cancer treatments impact quality of life and induce patients to excessive rest and lack of physical activity resulting in severe deconditioning. Exercise has been shown to increase performance status, strength, endurance and reduce emotional issues in lung cancer patients. Despite these benefit this approach is a poorly utilized strategy and several barriers must be overcome due to limited data, lack of awareness of the benefits of exercise, and limited patient motivation. Several programs of adapted physical activity are developing to support lung cancer patients during oncological treatments, adopting a personalized approaches. Rowing programs have been reported in cancer survivors to reduce risk factors and the impact of treatments complications, particularly lymphedema in breast cancer survivors. A pioneering program of adapted physical activity was developed by a multidisciplinary team in collaboration with an association for the support of cancer patients (Sicilian Association for Oncological Support), using rowing in patients with active metastatic cancer, to evaluate feasibility, response of patients, and to increase awareness of the benefits of physical activity in the fight against lung cancer. Methods: The program was launched in December 2019 from the idea of a young world rowing champion, but the advent of the COVID-19 pandemic led to the postponement of this project, which was subsequently developed from March 2021 to July 2021. The team was composed by oncologists, sports medicine specialists, two coaches specialised in adapted physical activity programs and a cardiologist. The voluntary logistic assistance was warranted by the rowing society “Canottieri Peloro”, which effectively allowed the project to be carried out, providing patients with equipment, a specialised team doctor and a well-equipped gym. In this preliminary experience we managed to include a small number of patients to assess the feasibility/validity of this approach and improve patients’ needs and satisfaction. Results: Four patients affected by metastatic lung adenocarcinoma with EGFR mutations joined the project (1 M/3 F;median age was 59.5, range 47-68;ECOG PS: 1). All patients presented well-controlled and mild symptoms related to the disease (cough, dyspnea, bone or chest pain) and were receiving active oncological treatments (first line EGFR-TKI: 2 patients;second line EGFR-TKI and maintenance chemotherapy). After a baseline clinical, oncological and cardiological evaluation personalized training program was developed. Briefly, indoor training and individual rowing sessions have been administered to patients. All patients reported full adherence to the training, developing a growing motivation and interest in improving physical performance. We did not recorded any worsening of symptoms or problems related to cancer treatments. The full contact with water and nature and the peculiar backwards motion of rowing had a positive impact on patients, that enjoyed the experience, reducing their anxiety for the future. Conclusions: This preliminary experience, previous developed as a support activity for lung cancer patients, might pave the way for further exploration of the role of rowing in this setting and promote a pivotal project to better define specific programs for metastatic cancer patients to improve compliance and response to cancer treatments. Keywords: Lung cancer, Adapted physical activity, Rowing

18.
Journal of Thoracic Oncology ; 17(9):S283, 2022.
Article in English | EMBASE | ID: covidwho-2031519

ABSTRACT

Introduction: Durvalumab received EMA approval as consolidation therapy (CT) for unresectable stage III NSCLC with PD-L1 ≥1% and who did not have progression after CRT. Our objective was to analyze in real clinical practice the effectiveness of durvalumab and explore the clinical factors that may be associated with the benefit from CT. Methods: Retrospective study was made at Hospital of Leon (Spain), including 37 patients with locally advanced NSCLC treated with durvalumab after CRT treatment between March 2018 and october 2021 (40.5% patients were included in the durvalumab early access program). The neutrophil-to-lymphocyte ratio (NLR) could identified after CRT as a factor that may be benefit from durvalumab. Results: Median age was 67 years (range 46-82 years). 40.5% of patients were ≥70 years old. 78.4% were male and 51.4% smokers. 54% had non-squamous histology. PD-L1 expression was <1% in 5% and not available in 8% patients. 2.7% ROS1 rearrangements, 5.4% KRAS mutations and not available in 43.2% patients. Stage IIIA, IIIB, IIIC disease were 24.3%, 54.1% and 21.6%, respectively. Median time from end of CRT to onset durvalumab was 44 days (range 13-120 days). Overall median CT duration was 214.8 days (range 69-399 days) with a median of 14 infusions (range 6-27 infusions). With a median follow up of 19.7 months (range 1.4-34.9 months);67.6% had stopped CT: 37.8% due to completing treatment, 16.2% disease progression, 10.8% adverse event and 2.7% due to COVID19 infection. Median real-world progression-free survival (rwPFS) was 17 months (95% CI, 11-23). Median real-world overall survival (rwOS) was 29.9 months (95% CI, 23.3-36.6). %rwOS at 6, 18 and 24 months were 100%, 86.9% and 74.5%, respectively. For patients with post-CRT NLR not exceeding the cohort median value of 6, receipt of durvalumab was associated with an improvement in rwOS (median not reached vs 25.7 months;p=0.025). 56.8% patients had any grade of radiation pneumonitis (median time from CRT start: 119 days [range 36-241 days]). Of these, 19% patients developed worsening of radiation pneumonitis with durvalumab. 54,1% developed immune-mediated toxicity, mostly G1-2 (85.1%). Conclusions: Our results demonstrate the effectiveness of durvalumab consolidation in this patients population in a real-life setting. We identified low NLR after CRT as a potentially predictive factor for the benefit of CT in locally advanced NSCLC. Keywords: DURVALUMAB, PACIFIC, REAL WORLD DATA

19.
Int J Biol Macromol ; 219: 980-997, 2022 Aug 08.
Article in English | MEDLINE | ID: covidwho-2031328

ABSTRACT

Omicron, another SARS-CoV-2 variant, has been recorded and reported as a VoC. It has already spread across >30 countries and is a highly mutated variant. We tried to understand the role of mutations in the investigated variants by comparison with previous characterized VoC. We have mapped the mutations in Omicron S-glycoprotein's secondary and tertiary structure landscape using bioinformatics tools and statistical software and developed different models. In addition, we analyzed the effect of diverse mutations in antibody binding regions of the S-glycoprotein on the binding affinity of the investigated antibodies. This study has chosen eight significant mutations in Omicron (D614G, E484A, N501Y, Q493K, K417N, S477N, Y505H G496S), and seven of them are located in the RBD region. We also performed a comparative analysis of the ΔΔG score of these mutations to understand the stabilizing or destabilizing properties of the investigated mutations. The analysis outcome shows that D614G, Q493K, and S477N mutations are stable mutations with ΔΔG scores of 0.351 kcal/mol, 0.470 kcal/mol, and 0.628 kcal/mol, respectively, according to DynaMut estimations. While other mutations (E484A, N501Y, K417N, Y505H, G496S) showed destabilizing results. The D614G, E484A, N501Y, K417N, Y505H, and G496S mutations increased the molecular flexibility of S-glycoprotein to interact with the ACE2 receptor, increasing the variant's infectivity. Our study will contribute to research on the SARS-CoV-2 variant, Omicron, by providing information on the mutational pattern and exciting properties of these eight significant mutations, such as antibody escape and infectivity quotient (stabilizing or destabilizing; increased or decreased molecular flexibility of S-glycoprotein to interact with the human ACE2 receptor).

20.
Journal of Thoracic Oncology ; 17(9):S130-S131, 2022.
Article in English | EMBASE | ID: covidwho-2031505

ABSTRACT

Introduction: There is a subset of NSCLC patients ineligible for benefit from TKIs/Immunotherapy (e.g. STK11 mutation conferring resistance to Immunotherapy). Besides, many patients cannot afford these therapies. Metformin has anticancer properties acting both on glycolytic metabolism and tumor microenvironment. In vitro studies suggest synergism between metformin and pemetrexed. STK11 deficient cell lines are more sensitive to metformin. Clinical studies combining metformin with chemotherapy are limited by small sample size. We conducted an exploratory phase-2 clinical trial of metformin with pemetrexed/carboplatin in advanced non-squamous NSCLC. Methods: This was a single center, open label, single arm phase 2 clinical trial with a Simon’s two stage design. The null hypothesis was that the combination would not improve the 6-month PFS rate by 15%, from 50%. Treatment-naive, non-diabetic patients aged 18-75 years with NSCLC (adenocarcinoma/not-otherwise-specified) with stage IV disease having ECOG PS 0-2 with unmutated EGFR/ALK and without brain metastasis or with asymptomatic brain metastases were treated with pemetrexed-carboplatin chemotherapy and metformin for six months. The primary outcome was 6-month progression free survival (PFS) rate. Secondary outcomes were safety, overall survival (OS), overall response rate (ORR), proportion of STK 11 mutation and effect of STK 11 mutation on 6-month PFS rate. PFS and OS were estimated using the Kaplan-Meier method. Targeted sequencing was attempted for available tissue specimens. Results: The first interim analysis was performed after enrollment of 26 patients for the first stage (before the target accrual of first stage was reached) due to slow accrual, in view of COVID pandemic. The study was terminated after first stage for futility. The median age of patients in the study was 52 years (range, 30 to 68) and 18 patients (69.0%) were males. Half of the patients had ECOG-PS 2. Brain metastases were present in eight (31%) patients and among these four (50%) were symptomatic at presentation. The median follow-up time was 25 months. The median PFS was four months. 6-month PFS rate was 28% (95% CI - 0.12 to 0.46). Of the 25 evaluable patients, five (20%) had a partial response, and eight (32%) had stable disease;13 (52%) of the patients had disease control. The median OS was 16 months. During combined therapy, 14 (54%) and 3 (11%) patients had any grade and grade 3 anemia respectively. One patient had grade 3 neutropenia. Among non-hematological toxicities, gastrointestinal toxicities (nausea, vomiting and diarrhea) were the most common. No grade 4 toxicities were reported. There were no treatment discontinuations, however treatment delay due to grade three toxicities was present in two patients. Dose modification for Metformin was required in four patients. Targeted Sequencing was possible in nine cases. Two of these patients had STK11 mutation and an associated bad outcome (PFS < 2 months). Conclusions: We could not demonstrate the benefit of combination of Metformin with pemetrexed-carboplatin in terms of improvement in 6-month PFS rate. The addition of metformin to pemetrexed-carboplatin has an acceptable safety profile. Future trials should test metformin in specific subsets (STK11 mutated) and in combination with immunotherapy and TKIs. Keywords: Metformin, NSCLC, STK11

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