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2022 ◽  
Vol 119 (3) ◽  
pp. e2114886119
Author(s):  
Wren E. Michaels ◽  
Cecilia Pena-Rasgado ◽  
Rusudan Kotaria ◽  
Robert J. Bridges ◽  
Michelle L. Hastings

CFTR gene mutations that result in the introduction of premature termination codons (PTCs) are common in cystic fibrosis (CF). This mutation type causes a severe form of the disease, likely because of low CFTR messenger RNA (mRNA) expression as a result of nonsense-mediated mRNA decay, as well as the production of a nonfunctional, truncated CFTR protein. Current therapeutics for CF, which target residual protein function, are less effective in patients with these types of mutations due in part to low CFTR protein levels. Splice-switching antisense oligonucleotides (ASOs), designed to induce skipping of exons in order to restore the mRNA open reading frame, have shown therapeutic promise preclinically and clinically for a number of diseases. We hypothesized that ASO-mediated skipping of CFTR exon 23 would recover CFTR activity associated with terminating mutations in the exon, including CFTR p.W1282X, the fifth most common mutation in CF. Here, we show that CFTR lacking the amino acids encoding exon 23 is partially functional and responsive to corrector and modulator drugs currently in clinical use. ASO-induced exon 23 skipping rescued CFTR expression and chloride current in primary human bronchial epithelial cells isolated from a homozygote CFTR-W1282X patient. These results support the use of ASOs in treating CF patients with CFTR class I mutations in exon 23 that result in unstable CFTR mRNA and truncations of the CFTR protein.


Plant Disease ◽  
2022 ◽  
Author(s):  
Helga Forster ◽  
Yong Luo ◽  
Lingling Hou ◽  
James Adaskaveg

Alternaria leaf spot caused by Alternaria alternata and A. arborescens is a common disease of almond in California. Succinate dehydrogenase inhibitors (SDHIs) are widely used for its management, however, we observed reduced performance of SDHI fungicides at some field sites. Thus, we evaluated the sensitivity of 520 isolates of the main pathogen A. alternata from major production areas collected between 2006 and 2019 to boscalid and of a subset of 204 isolates to six members of the SDHIs belonging to six sub-groups. Additionally, 97 isolates (14 sensitive and 83 with reduced sensitivity) of the 204 were used to determine the molecular mechanisms of resistance. A wide range of in vitro concentrations to effectively inhibit mycelial growth by 50% (EC50 values) was determined for each fungicide using the spiral gradient dilution method. Some isolates were highly resistant (EC50 values >10 μg/ml) to boscalid (a pyridine-carboxamide), pyraziflumid (a pyrazine-carboxamide), and fluxapyroxad (a pyrazole-4-carboxamide), but not to fluopyram (a pyridinyl-ethyl-benzamide), isofetamid (a phenyl-oxo-ethyl thiophene amide), and pydiflumetofen (a N-methoxy-(phenyl-ethyl)-pyrazole-carboxamide). There was no strong cross resistance among the fungicides tested, including for the two pyrazole-4-carboxamides fluxapyroxad and penthiopyrad (tested for 33 of the 204 isolates). The comparison of EC50 values for fluopyram and isofetamid resulted in the highest coefficient of determination (R2 = 0.582) among ten pairwise comparisons between sub-groups. Sequence analyses of the 97 isolates revealed five mutations in SdhB, SdhC, or SdhD subunits of the Sdh target gene among 73 isolates with reduced sensitivity to at least one SDHI. No mutations were detected in the 14 sensitive isolates and in 10 of the 83 isolates with reduced sensitivity. The most common mutation (59 isolates) was H134R in SdhC. Other mutations included H277Y (8 isolates) and H277L (2 isolates) in SdhB, as well as G79R (2 isolates) and S135R (2 isolates) in SdhC. Mutations H277Y in SdhB and S135R in SdhC were only present in isolates collected in 2012 or earlier. Both conferred mostly high levels of resistance to boscalid and also reduced sensitivity to pyraziflumid, fluxapyroxad, and isofetamid with intermediate EC50 levels. Mutations H277L in SdhB, as well as H134R and G79R in SdhC, that were found in isolates obtained after 2012 had very similar resistance phenotypes with different levels of resistance to boscalid, pyraziflumid, and fluxapyroxad, whereas sensitivity to fluopyram, isofetamid, and pydiflumetofen was mostly less affected. Our data for SDHI fungicides do not support the classical concept of positive cross resistance within a single mode of action. Because some mutations conferred resistance to multiple SDHI sub-groups, however, resistance management needs to consider all SDHIs as a homogenous group that should be mixed or rotated with other modes of action prior to resistance development to either mode of action.


Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6309
Author(s):  
Hira Shaikh ◽  
Julie E. McGrath ◽  
Brittany Hughes ◽  
Joanne Xiu ◽  
Pavel Brodskiy ◽  
...  

Recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients overall have a poor prognosis. However, human papillomavirus (HPV)-associated R/M oropharyngeal squamous cell carcinoma (OPSCC) is associated with a better prognosis compared to HPV−negative disease. Immune checkpoint blockade (ICB) is the standard of care for R/M HNSCC. However, whether HPV and its surrogate marker, p16, portend an improved response to ICB remains controversial. We queried the Caris Life Sciences CODEai database for p16+ and p16− HNSCC patients using p16 as a surrogate for HPV. A total of 2905 HNSCC (OPSCC, n = 948) cases were identified. Of those tested for both HPV directly and p16, 32% (251/791) were p16+ and 28% (91/326) were HPV+. The most common mutation in the OPSCC cohort was TP53 (33%), followed by PIK3CA (17%) and KMT2D (10.6%). TP53 mutations were more common in p16− (49%) versus the p16+ group (10%, p < 0.0005). Real-world overall survival (rwOS) was longer in p16+ compared to p16− OPSCC patients, 33.3 vs. 19.1 months (HR = 0.597, p = 0.001), as well as non-oropharyngeal (non-OP) HNSCC patients (34 vs. 17 months, HR 0.551, p = 0.0001). There was no difference in the time on treatment (TOT) (4.2 vs. 2.8 months, HR 0.796, p = 0.221) in ICB-treated p16+ vs. p16− OPSCC groups. However, p16+ non-OP HNSCC patients treated with ICB had higher TOT compared to the p16− group (4.3 vs. 3.3 months, HR 0.632, p = 0.016), suggesting that p16 may be used as a prognostic biomarker in non-OP HNSCC, and further investigation through prospective clinical trials is warranted.


2021 ◽  
Author(s):  
Andrew S. Bray ◽  
Richard D. Smith ◽  
Andrew W. Hudson ◽  
Giovanna E. Hernandez ◽  
Taylor M. Young ◽  
...  

AbstractDue to its high transmissibility, Klebsiella pneumoniae (Kpn) is one of the leading causes of nosocomial infections. Here, we studied the biological cost of colistin resistance, an antibiotic of last resort, of this opportunistic pathogen using a murine model of gut colonization and transmission. Colistin resistance in Kpn is commonly the result of inactivation of the small regulatory protein MgrB. Without a functional MgrB, the two-component system PhoPQ is constitutively active, leading to increased lipid A modifications and subsequent colistin resistance. Using an engineered MgrB mutant, we observed that MgrB-dependent colistin resistance is not associated with a fitness defect during in vitro growth conditions. However, colistin-resistant Kpn colonizes the murine gut poorly, which may be due to the decreased production of capsular polysaccharide by the mutant. The colistin-resistant mutant of Kpn had increased survival outside the host when compared to the parental colistin-sensitive strain. We attribute this enhanced survivability to dysregulation of the PhoPQ two-component system and accumulation of the master stress regulator RpoS. The enhanced survival of the colistin resistant strain may be a key factor in the observed rapid host-to-host transmission in our model. Together, our data demonstrate that colistin-resistant Kpn experiences a biological cost in gastrointestinal colonization. However, this cost is mitigated by enhanced survival outside the host, increasing the risk of transmission. Additionally, it underscores the importance of considering the entire life cycle of a pathogen to truly determine the biological cost associated with antibiotic resistance.ImportanceThe biological cost associated with colistin resistance in Klebsiella pneumoniae (Kpn) was examined using a murine model of Kpn gut colonization and fecal-oral transmission. A common mutation resulting in colistin resistance in Kpn is a loss-of-function mutation of the small regulatory protein MgrB that regulates the two-component system PhoPQ. Even though colistin resistance in Kpn comes with a fitness defect in gut colonization, it increases bacterial survival outside the host enabling it to more effectively transmit to a new host. The enhanced survival is dependent upon the accumulation of RpoS and dysregulation of the PhoPQ. Hence, our study expands our understanding of the underlying molecular mechanism contributing to the transmission of colistin-resistant Kpn.


2021 ◽  
Vol 12 ◽  
Author(s):  
Mengge Yang ◽  
Lusi Xu ◽  
Chunmei Xu ◽  
Yuying Cui ◽  
Shan Jiang ◽  
...  

AimsTo investigate the clinical features and mitochondrial mutations for maternally inherited diabetes and deafness.MethodsPubMed, Embase, Medline, Web of Science, the China National Knowledge Infrastructure, and Wanfang were searched with the following search terms: “Maternally inherited diabetes and deafness” OR “MIDD” OR “Mitochondrial diabetes”. The mutations and clinical features were analyzed. Correlation between the heteroplasmy levels of the m.3243A&gt;G mutation in the peripheral blood and age at the onset of diabetes was conducted by Spearman test. The significance level was set as p &lt; 0.05. Statistical analysis was performed using the Statistical Package for the Social Sciences version 26 for Windows.ResultsTotally 161 patients with 21 different mitochondrial mutations were enrolled. The most common mutation was the m.3243A&gt;G mutation in 136 cases. Of 142 patients, 120 (84.51%) had family histories of diabetes or hearing loss. Hearing loss presented in 85.71% of the patients with mitochondrial mutations. Central nervous system diseases were found in 29.19%, myopathy in 22.98%, oculopathy in 23.60%, cardiac disease in 23.60%, and nephropathy in 13.66% of the patients. Forty-two of 101 (41.58%) patients were underweight. A significant negative correlation was found between the heteroplasmy levels of the m.3243A&gt;G mutation in the peripheral blood and age at the onset of diabetes.ConclusionsThe young onset of diabetes with low or normal BMI, maternal inheritance, and presence of impairments of multiple systems should prompt a genetic testing in order to differentiate MIDD from other types of diabetes earlier.


2021 ◽  
Vol 26 (10) ◽  
pp. 4590
Author(s):  
K. V. Savostyanov ◽  
E. N. Basargina ◽  
E. E. Ryabova ◽  
A. A. Pushkov ◽  
I. S. Zhanin ◽  
...  

Aim. To identify the proportion of restrictive cardiomyopathy (RCM), as well as cardiomyopathy (CMP) with a restrictive type of hemodynamics among all cases of genetic CMP and to determine the relative frequencies and spectrum of nucleotide variants in Russian children with RCM, as well as to search for phenogenotypic correlations.Material and methods. The study included 689 children with CMPs. All children underwent a molecular genetic testing of the target regions of 419 genes responsible for various cardiomyopathies and channelopathies using the method of massively parallel sequencing (MPS).Results. In 668 (97,0%) children, pathogenic, likely pathogenic nucleotide variants, as well as nucleotide variants with unknown clinical significance, were identified. Of these, 45 (6,7%) patients were selected to determine the molecular genetic characteristics of RCM, 20 of whom had clinical symptoms and morphofunctional structure of RCMP (3,0%), while the remaining 25 (3,7%) children were diagnosed with another CMP type with a restrictive type of hemodynamics. In total, these patients had 41 nucleotide variants in 15 different genes, while 19 (46,3%) variants were pathogenic, 12 (29,3%) — likely pathogenic, 10 (24,4%) — uncertain clinical significance. Pathogenic and likely pathogenic variants were identified in a total of 38 (84,4%) patients, while in 19 (42,2%) patients, the pathogenic variants described earlier were found. The most common genetic marker of RCM in Russian children was TNNI3 gene mutations. In total, they were identified in 12 (25%) children: with RCP — 8 (40%) patients; with CMP with a restrictive type of hemodynamics — 4 (16%) patients. At the same time, the most common mutation of the TNNI3 gene was the nucleotide variant c.575G>A, leading to the amino acid variant p.R192H, described earlier in patients with RCM and identified by us in three (15%) unrelated children with RCM. In addition, a significant difference was found between the averaged values of N-terminal pro-brain natriuretic peptide in patients with mutations in the MYH7 and TNNI3 genes (0,0039, p<0,05), as well as between the peak flow gradient values in children with mutations in TNNI3 and FLNC genes (0,0016, p<0,05), TNNI3 and MYH7 genes (0,039, p<0,05).Conclusion. The results of this study indicate a significant genetic heterogeneity of RCM in Russian children and the need for further research aimed at finding genotype-phenotype associations in order to predict the course of the disease and select the proper therapy.


2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Selahaddin Tekeş ◽  
Diclehan Oral ◽  
Murat Söker ◽  
Selda Şimşek ◽  
Veysiye Hülya Uzel ◽  
...  

Abstract Objectives Hemoglobin disorders are quite heterogeneous in the Turkish population. Up to now, more than forty different beta thalassemia mutations and 60 hemoglobin variants have been characterized in the country. The aim of this study was to investigate genetic heterogeneity of HBB gene mutations in patients and their parents at Southeastern Anatolia in Turkey. Methods Genomic DNA was isolated from 145 thalassemic patients’ blood samples and their parents in this study. Ten different HBB gene mutations HBB:c.-80T>A, HBB:c.17_18delCT, HBB:c.25_26delAA, HBB:c.92+1G>A, HBB:c.92+5G>C, HBB:c.92+6T>C, HBB:c.93-21G>A, HBB:c.135delC, HBB:c.315+1G>A, HBB:c.316-106C>G were screened by amplification refractory mutation system. Four Hb variants and some rare beta thalassemia mutation were characterized by DNA sequencing. Results In this study, 97 homozygous and 48 compound heterozygous thalassemic patients were diagnosed by molecular genetic analyses. As a results, 18 β-thalassemia mutations and four abnormal hemoglobins; HBB:c.20A>T, HBB:c.364G>C, HBB:c.34G>A and HBB:c.208G>A were detected at Dicle University Hospital. Conclusions In the results, HBB:c.93-21G>A is the most common mutation in the region. Three mutations [(HBB:c.93-21G>A), (HBB:c.25_26delAA) and (HBB:c.135delC)] account for about 58 per cent of all the point mutations. Except HBB:c.20A>T and HBB:c.364G>C, two silent Hb variants (HBB:c.34G>A and HBB:c.208G>A) were detected in this study. Hb Hamilton [β11 (GTT>ATT) Val>Ile] was seen first time in Turkey.


Author(s):  
Mira Tafa ◽  
Sevim Naz Karışık ◽  
Ece Begüm Aksoy ◽  
Rüya Aslan

Cystic Fibrosis is a rare genetic disease that affects the transmission of chloride ions due to mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. Even though there are nearly 2000 mutations identified to be related to the condition, the most common mutation is F508del; deletion of a phenylalanine residue at 508. On the other hand, G542X which is a Class I mutation is also found very commonly and there are no modulator treatments available for it. Furthermore, it was investigated that R553X mutation can as well be corrected simultaneously with G542X mutation. Therefore, the main focus is on designing a gene therapy project that can correct all these three mutations at once by utilizing the prime editing technique via lipid-based delivery. In this way, the mutations can be edited through plasmids that were designed containing 2 pegRNAs and the Cas enzyme. To implement such an approach efficiently, both ex vivo, an animal model, and in vivo steps are to be designed. For the cell line, fibroblasts are selected due to their simplicity and low cost. The animal model of the experiment is determined to be a ferret concerning the high similarity to the human's CFTR protein and finally, the procedure will follow on a direct application in human Cystic Fibrosis patients. The plasmids are thought to be delivered through a cationic liposome that will reach the lungs with the aid of a nebulizer. At the last stage of the experimental procedure, Sanger Sequencing will be done to see if the desired edit within the CFTR has been performed successfully, and Next Generation Sequencing will be executed to see if there has been an off-target mutation in the remainder of the genome. Whereas for detecting the presence and expression of CFTR protein in humans, immunodetection with flow cytometry will be conducted.


2021 ◽  
Author(s):  
Yanxin Chen ◽  
Yongzhi Zheng ◽  
Yunda Hong ◽  
Jingjing Wen ◽  
Jiazheng Li ◽  
...  

Abstract Prognosis of acute lymphoblastic leukemia (ALL) in adults is inferior to children. Hence, ALL is still a challenging disease to be cured in adult population. Aberrant genetic alterations have been observed previously in ALL, while the patterns of differential gene alteration have not much been comprehensively determined in the adult and pediatric ALL on a genome-wide scale. This study was attempted to investigate the biological differences in genomic profiling between the adults and children with ALL, and the relationship between the genomic heterogeneity and prognosis. The results showed the similar common mutation types in two populations but the increased prevalence of genetic alterations in adult ALL. The median number of detected gene mutations was 17 (range: 1–53) per sample in adult ALL and 4.5 (range: 1–19) in pediatric ALL(P<0.001). A significant correlation between the increased number of gene mutations and age was found (R2 = 0.5853, P<0.001). 122 and 53 driver genes were identified in adult and pediatric ALL samples, respectively. The IKZF1, IDH1 and TTN mutations were significantly enriched in adult ALL. The incidence of relapse was 40.0% and 9.6% in the adult and pediatric ALL, respectively(P=0.0003). The overall survival (OS) and relapse free survival (RFS) of adult ALL were poorer than pediatric ALL (P=0.0002, P<0.001, respectively). This genomic landscape enhanced the understanding of the biological differences of ALL between the two populations and provided a clue for novel therapeutic approaches.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4370-4370
Author(s):  
Joan Oliva ◽  
Larakaye Villanueva ◽  
Jun Ochiai ◽  
Yutaka Niihara

Abstract Waldenstrom Macroglobulinemia (WM) is a non-Hodgkin lymphoma, often associated with production of monoclonal IgM in a large amount. The increased level of IgM leads to the increased level of blood viscosity, potentially causing spontaneous bleeding, headaches, vertigo and could lead to stroke and coma. WM is a rare disease, affecting around 3 cases per million per year in the USA. Different chromosomal abnormalities can be cause of WM, but the most common mutation detected in WM is the mutation L265P on the Myd88 protein, a downstream regulator of TLR4 pathway. While today there are many treatment options to manage WM, including plasmapheresis, monoclonal (rituximab) and immunomodulating drugs (halidomide), cytokines, mTOR inhibitors (everolimus), Burton tyrosine kinase (Ibrutinib), there isn't a single effective enough treatment for WM that are widely used. In this study, MWCL-1 cells (adult WM), expressing the Myd88 L265P mutation, were used to test different drugs to monitor their effect in cell proliferation and apoptosis activities, in comparison to midostaurin (an inhibitor of FLT3), for 24 hours treatment. MWCL-1 cells were cultured in RPMI1640, in presence of 2, 10 and 25 % of fetal bovine serum (FBS). 25 % FBS was tested to be as close as possible with the level of serum present in human blood. Adipose stromal cells (ASC) were used as a reference control, in absence of serum. Compounds A (targeting TLR pathway, through IRAK-4) was used at various concentrations (0.05 to 100 µM), over 24h of treatment, in combination or not with compound B (targeting the DNA). Compound A has a high affinity for IRAK4, downstream kinase of TLR pathway. TLR pathway activation in leukemia, through Myd88 and IRAK4, is involved in the pro-inflammation response but it is also inducing proliferation and cell survival. Compound B is an inhibitor of the poly (ADP-ribose) polymerase (PARP), which are enzymes that are involved in DNA transcription, cell cycle regulation and DNA repair. In the ASC, the caspase activity of compound A was not different from the control, but the number of cells was lower at 50 and 100 µM, indicating that the compound A was delaying the cell growth. The number of MWCL-1 cells decreased only at higher compound A concentration (50 and 100 µM), during a 24h treatment, at 2, 10 and 25 % FBS. When the cells were treated with the compound A, the level of caspase 3/7 activity was elevated only at the highest concentration (50 and 100 µM), which is consistent with the decreased number of cells, at 2, 10 and 25 % FBS. MWCL-1 were more resistant to the anti-cancer effect of the compound A at 25 % FBS, indicating that it could work on patients because 25 % FBS is close to the patient's serum level. Midostaurin, from 0.05 to 100 µM, was reducing the number of cells and increasing the caspase 3/7 activity in the cells, in a dose response manner, at 2, 10 and 25 % FBS. However, data suggest that at the highest midostaurin dose (100 µM), compound A was more efficient than midostaurin (100 µM). Compound B alone, at 10 µM, had no effect on the MWCL-1 cell number and on the caspase 3/7 activity, for the 2, 10 and 25 % FBS. However, a synergistic effect was demonstrated when compound B (10 µM) was combined with compound A at 50 and 100 µM. The combination decreased the number of MWCL-1 cells and increased the caspase activity 3/7, more so than it was compared to the single compound studies. Our data suggest that it would be possible to lower the posology of the compound A when it will be given to the patients, in combination with the compound B. In conclusion, the data showed compound A alone or combined with the compound B decreased the level of proliferation and increased the level of apoptosis of MWCL-1 cells, cultured with 2 to 25 % of FBS. The use of compound A at high concentration to reduce the number of MWCL-1 reflect the difficulties to treat WM patient with the existing approved drugs. Further studies will be necessary to understand more the molecular mechanism affected by the compound A and/or B in the TLR-IRAK4 pathway, and to study their effect in vivo. Disclosures Oliva: Emmaus Lifesciences, Inc.: Current Employment. Villanueva: Emmaus Lifesciences, Inc.: Current Employment. Ochiai: Emmaus Lifesciences, Inc.: Ended employment in the past 24 months. Niihara: Emmaus Lifesciences, Inc.: Current Employment.


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