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JCO Precision Oncology Aug 2022Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified... (Meta-Analysis)
Meta-Analysis
PURPOSE
Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established.
METHODS
We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration-approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, and MAPK TT type. Coprimary outcomes were response rate and progression-free survival.
RESULTS
A total of 18,167 studies were screened, identifying 80 studies with 238 patients who met inclusion criteria. This included 167 patients with class 2 and 71 patients with class 3 BRAF mutations. Overall, 77 patients achieved a treatment response. In both univariate and multivariable analyses, response rate and progression-free survival were higher among patients with class 2 compared with class 3 mutations, findings that remain when analyses are restricted to patients with melanoma or lung primary cancers. MEK ± BRAF inhibitors demonstrated greater clinical activity in class 2 compared with class 3 BRAF-mutant tumors than BRAF or EGFR inhibitors.
CONCLUSION
This meta-analysis suggests that MAPK TTs have clinical activity in some class 2 and 3 BRAF-mutant cancers. BRAF class may dictate responsiveness to current and emerging treatment strategies, particularly in melanoma and lung cancers. Together, this analysis provides clinical validation of predictions made on the basis of a mutation classification system established in the preclinical literature. Further evaluation with prospective clinical trials is needed for this population.
Topics: Humans; Lung Neoplasms; Melanoma; Mitogen-Activated Protein Kinases; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; United States
PubMed: 35977349
DOI: 10.1200/PO.22.00107 -
Interdisciplinary Perspectives on... 2022Tuberculosis (TB) is one of the top 10 causes of mortality and the first killer among infectious diseases of poverty (IDoPs) worldwide. It disproportionately affects...
Tuberculosis (TB) is one of the top 10 causes of mortality and the first killer among infectious diseases of poverty (IDoPs) worldwide. It disproportionately affects on-third of the world's low-income countries including Ethiopia. One of the factors driving the TB epidemic is the global rise of MDR/XDR-TB and their low detection affect the global TB control progress. Recently, the resistance-associated genetic mutations in MTBC known to confer drug resistance have been detected by rapid molecular diagnostic tests and sequencing methods. In this article, the published literature searched by PubMed database from 2010 to 2021 and English language were considered. The aim of this systematic review was to assess the prevalence of the most common rpoB, katG, and inhA gene mutations associated with multidrug resistance in MTBC clinical strains among TB patients in Ethiopia. Though 22 studies met our eligibility criteria, only 6 studies were included in the final analysis. Using the molecular GenoType MTBDRplus and MTBDRsl line probe assay and sequencing procedures, a total of 932 culture-positive MTBC isolates were examined to determine RIF, INH, and MDR-TB resistance patterns along with rpoB, katG, and inhA gene mutation analysis. As a result, among the genotypically tested MTBC isolates, 119 (12.77%), 83 (8.91%), and 73 (7.32%) isolates were INH, RIF, and MDR-TB resistant, respectively. In any RIF-resistant MTBC strains, the most common single point mutations were in codon 531 (S531L) followed by codon 526 (H526Y) of the rpoB gene. Besides, the most common mutations in any INH-resistant MTBC were strains observed at codon 315 (S315T) and WT probe in the katG gene and at codon C15T and WT1 probe in the inhA promoter region. Detection of resistance allele in rpoB, KatG, and inhA genes for RIF and INH could serve as a marker for MDR-TB strains. Tracking the most common S531L, S315T, and C15T mutations in rpoB, katG, and inhA genes among RIF- and INH-resistant isolates would be valuable in TB diagnostics and treatment regimens, and could reduce the development and risk of MDR/XDR-TB drug-resistance patterns.
PubMed: 35757683
DOI: 10.1155/2022/1967675 -
RSC Advances Mar 2022The novel human coronavirus pandemic is one of the most significant occurrences in human civilization. The rapid proliferation and mutation of Severe Acute Respiratory... (Review)
Review
The novel human coronavirus pandemic is one of the most significant occurrences in human civilization. The rapid proliferation and mutation of Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) have created an exceedingly challenging situation throughout the world's healthcare systems ranging from underdeveloped countries to super-developed countries. The disease is generally recognized as coronavirus disease 2019 (COVID-19), and it is caused by a new human CoV, which has put mankind in jeopardy. COVID-19 is death-dealing and affects people of all ages, including the elderly and middle-aged people, children, infants, persons with co-morbidities, and immunocompromised patients. Moreover, multiple SARS-CoV-2 variants have evolved as a result of genetic alteration. Some variants cause severe symptoms in patients, while others cause an unusually high infection rate, and yet others cause extremely severe symptoms as well as a high infection rate. Contrasting with a previous epidemic, COVID-19 is more contagious since the spike protein of SARS-CoV-2 demonstrates profuse affection to angiotensin-converting enzyme II (ACE2) that is copiously expressed on the surface of human lung cells. Since the estimation and tracking of viral loads are essential for determining the infection stage and recovery duration, a quick, accurate, easy, cheap, and versatile diagnostic tool is critical for managing COVID-19, as well as for outbreak control. Currently, Reverse Transcription Polymerase Chain Reaction (RT-PCR) testing is the most often utilized approach for COVID-19 diagnosis, while Computed Tomography (CT) scans of the chest are used to assess the disease's stages. However, the RT-PCR method is non-portable, tedious, and laborious, and the latter is not capable of detecting the preliminary stage of infection. In these circumstances, nano-biosensors can play an important role to deliver point-of-care diagnosis for a variety of disorders including a wide variety of viral infections rapidly, economically, precisely, and accurately. New technologies are being developed to overcome the drawbacks of the current methods. Nano-biosensors comprise bioreceptors with electrochemical, optical, or FET-based transduction for the specific detection of biomarkers. Different types of organic-inorganic nanomaterials have been incorporated for designing, fabricating, and improving the performance and analytical ability of sensors by increasing sensitivity, adsorption, and biocompatibility. The particular focus of this review is to carry out a systematic study of the status and perspectives of synthetic routes for nano-biosensors, including their background, composition, fabrication processes, and prospective applications in the diagnosis of COVID-19.
PubMed: 35424900
DOI: 10.1039/d2ra01293f -
Journal of the Peripheral Nervous... Jun 2022Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy characterised by a high clinical and genetic heterogeneity. While most cases were... (Review)
Review
BACKGROUND AND AIMS
Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy characterised by a high clinical and genetic heterogeneity. While most cases were described in populations with Caucasian ancestry, genetic research on CMT in Africa is scant. Only a few cases of CMT have been reported, mainly from North Africa. The current study aimed to summarise available data on CMT in Africa, with emphasis on the epidemiological, clinical, and genetic features.
METHODS
We searched PubMed, Scopus, Web of Sciences, and the African Journal Online for articles published from the database inception until April 2021 using specific keywords. A total of 398 articles were screened, and 28 fulfilled our selection criteria.
RESULTS
A total of 107 families totalling 185 patients were reported. Most studies were reported from North Africa (n = 22). The demyelinating form of CMT was the commonest subtype, and the phenotype varied greatly between families, and one family (1%) of CMT associated with hearing impairment was reported. The inheritance pattern was autosomal recessive in 91.2% (n = 97/107) of families. CMT-associated variants were reported in 11 genes: LMNA, GDAP1, GJB1, MPZ, MTMR13, MTMR2, PRX, FGD4/FRABIN, PMP22, SH3TC2, and GARS. The most common genes reported are LMNA, GDAP1, and SH3TC2 and have been found mostly in Northern African populations.
INTERPRETATION
This study reveals that CMT is not rare in Africa, and describes the current clinical and genetic profile. The review emphasised the urgent need to invest in genetic research to inform counselling, prevention, and care for CMT in numerous settings on the continent.
Topics: Africa; Charcot-Marie-Tooth Disease; Genes, Recessive; Humans; Microfilament Proteins; Mutation; Phenotype; Proteins
PubMed: 35383421
DOI: 10.1111/jns.12489 -
Osong Public Health and Research... Feb 2022Yersinia pestis, the cause of plague and a potential biological weapon, has always been a threatening pathogen. Some strains of Y. pestis have varying degrees of...
Yersinia pestis, the cause of plague and a potential biological weapon, has always been a threatening pathogen. Some strains of Y. pestis have varying degrees of antibiotic resistance. Thus, this systematic review was conducted to alert clinicians to this pathogen's potential antimicrobial resistance. A review of the literature was conducted for experimental reports and systematic reviews on the topics of plague, Y. pestis, and antibiotic resistance. From 1995 to 2021, 7 Y. pestis isolates with 4 antibiotic resistance mechanisms were reported. In Y. pestis 17/95, 16/95, and 2180H, resistance was mediated by transferable plasmids. Each plasmid contained resistance genes encoded within specific transposons. Strain 17/95 presented multiple drug resistance, since plasmid 1202 contained 10 resistance determinants. Strains 16/95 and 2180H showed single antibiotic resistance because both additional plasmids in these strains carried only 1 antimicrobial determinant. Strains 12/87, S19960127, 56/13, and 59/13 exhibited streptomycin resistance due to an rpsl gene mutation, a novel mechanism that was discovered recently. Y. pestis can acquire antibiotic resistance in nature not only via conjugative transfer of antimicrobial-resistant plasmids from other bacteria, but also by gene point mutations. Global surveillance should be strengthened to identify antibiotic-resistant Y. pestis strains by whole-genome sequencing and drug susceptibility testing.
PubMed: 35255676
DOI: 10.24171/j.phrp.2021.0288 -
Omics : a Journal of Integrative Biology Jan 2022Hearing impairment (HI) is a silent planetary health crisis that requires attention worldwide. The prevalence of HI in South Africa is estimated as 5.5 in 100 live...
Hearing impairment (HI) is a silent planetary health crisis that requires attention worldwide. The prevalence of HI in South Africa is estimated as 5.5 in 100 live births, which is about 5 times higher than the prevalence in high-income countries. This also offers opportunity to drive progressive science, technology and innovation policy, and health systems. We present here a systematic analysis and review on the prevalence, etiologies, clinical patterns, and genetics/genomics of HI in South Africa. We searched PubMed, Scopus, African Journals Online, AFROLIB, and African Index Medicus to identify the pertinent studies on HI in South Africa, published from inception to April 30, 2021, and the data were summarized narratively. We screened 944 records, of which 27 studies were included in the review. The age at diagnosis is ∼3 years of age and the most common factor associated with acquired HI was middle ear infections. There were numerous reports on medication toxicity, with kanamycin-induced ototoxicity requiring specific attention when considering the high burden of tuberculosis in South Africa. The Waardenburg Syndrome is the most common reported syndromic HI. The Usher Syndrome is the only syndrome with genetic investigations, whereby a founder mutation was identified among black South Africans (-c.6377delC). and genes are not major contributors to nonsyndromic HI among Black South Africans. Furthermore, emerging data using targeted panel sequencing have shown a low resolution rate in Black South Africans in known HI genes. Importantly, mutations in known nonsyndromic HI genes are infrequent in South Africa. Therefore, whole-exome sequencing appears as the most effective way forward to identify variants associated with HI in South Africa. Taken together, this article contributes to the emerging field of planetary health genomics with a focus on HI and offers new insights and lessons learned for future roadmaps on genomics/multiomics and clinical studies of HI around the world.
Topics: Deafness; Genomics; Hearing Loss; Humans; Mutation; South Africa
PubMed: 35041532
DOI: 10.1089/omi.2021.0181 -
Cancers Jun 2021Tumor mutational burden (TMB) is a numeric index that expresses the number of mutations per megabase (muts/Mb) harbored by tumor cells in a neoplasm. TMB can be... (Review)
Review
Tumor mutational burden (TMB) is a numeric index that expresses the number of mutations per megabase (muts/Mb) harbored by tumor cells in a neoplasm. TMB can be determined using different approaches based on next-generation sequencing. In the case of high values, it indicates a potential response to immunotherapy. In this systematic review, we assessed the potential predictive role of high-TMB in pancreatic ductal adenocarcinoma (PDAC), as well as the histo-molecular features of high-TMB PDAC. High-TMB appeared as a rare but not-negligible molecular feature in PDAC, being present in about 1.1% of cases. This genetic condition was closely associated with mucinous/colloid and medullary histology ( < 0.01). PDAC with high-TMB frequently harbored other actionable alterations, with microsatellite instability/defective mismatch repair as the most common. Immunotherapy has shown promising results in high-TMB PDAC, but the sample size of high-TMB PDAC treated so far is quite small. This study highlights interesting peculiarities of PDAC harboring high-TMB and may represent a reliable starting point for the assessment of TMB in the clinical management of patients affected by pancreatic cancer.
PubMed: 34206554
DOI: 10.3390/cancers13133119 -
Neurology Research International 2021Sickle cell anemia (SCA) is an inherited autosomal recessive disease. It is caused due to point mutation that substitutes glutamate with valine at the sixth amino acid... (Review)
Review
Sickle cell anemia (SCA) is an inherited autosomal recessive disease. It is caused due to point mutation that substitutes glutamate with valine at the sixth amino acid position of the beta chain of hemoglobin molecules leading to the sickling of the red blood cells and decreased structural deformability. Silent cerebral infarcts are the most common neurological complication of SCA, while overt stroke comprises substantial burden in patients with SCA. This meta-analysis aimed to find the pooled prevalence of overt stroke in SCA patients and discuss the importance of screening them. PubMed, Embase, and Google Scholar were the electronic databases used to search the studies. A total of 765 articles were retrieved upon detailed searching in the abovementioned databases. After a series of removing duplicate articles, title and abstract screening, and full-text review, 20 articles were found eligible and included in the study. The total number of participants from all the included studies was 3,956, and pooled prevalence of stroke in patients with sickle cell anemia in Asia was found to be 5% (95% CI: 4%, 6%) with a range from 1 to 41%. Stroke occurrence in sickle cell anemia patients is an emergency complication that needs immediate intervention and management. Because of the high prevalence of stroke in patients with sickle cell anemia, clinicians should focus on its prevention and treatment strategies.
PubMed: 34150339
DOI: 10.1155/2021/9961610 -
The Cochrane Database of Systematic... Feb 2021Eczema and food allergy are common health conditions that usually begin in early childhood and often occur together in the same people. They can be associated with an... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Eczema and food allergy are common health conditions that usually begin in early childhood and often occur together in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is effective in preventing eczema or food allergy.
OBJECTIVES
Primary objective To assess effects of skin care interventions, such as emollients, for primary prevention of eczema and food allergy in infants Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions that are associated with the greatest treatment benefit or harm for both eczema and food allergy.
SEARCH METHODS
We searched the following databases up to July 2020: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We searched two trials registers and checked reference lists of included studies and relevant systematic reviews for further references to relevant randomised controlled trials (RCTs). We contacted field experts to identify planned trials and to seek information about unpublished or incomplete trials.
SELECTION CRITERIA
RCTs of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy term (> 37 weeks) infants (0 to 12 months) without pre-existing diagnosis of eczema, food allergy, or other skin condition were included. Comparison was standard care in the locality or no treatment. Types of skin care interventions included moisturisers/emollients; bathing products; advice regarding reducing soap exposure and bathing frequency; and use of water softeners. No minimum follow-up was required.
DATA COLLECTION AND ANALYSIS
This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E-mediated food allergy by one to three years, both measured by the closest available time point to two years. Secondary outcomes included adverse events during the intervention period; eczema severity (clinician-assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen.
MAIN RESULTS
This review identified 33 RCTs, comprising 25,827 participants. A total of 17 studies, randomising 5823 participants, reported information on one or more outcomes specified in this review. Eleven studies randomising 5217 participants, with 10 of these studies providing IPD, were included in one or more meta-analysis (range 2 to 9 studies per individual meta-analysis). Most studies were conducted at children's hospitals. All interventions were compared against no skin care intervention or local standard care. Of the 17 studies that reported our outcomes, 13 assessed emollients. Twenty-five studies, including all those contributing data to meta-analyses, randomised newborns up to age three weeks to receive a skin care intervention or standard infant skin care. Eight of the 11 studies contributing to meta-analyses recruited infants at high risk of developing eczema or food allergy, although definition of high risk varied between studies. Durations of intervention and follow-up ranged from 24 hours to two years. We assessed most of this review's evidence as low certainty or had some concerns of risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so. Evidence for the primary food allergy outcome was rated as high risk of bias due to inclusion of only one trial where findings varied when different assumptions were made about missing data. Skin care interventions during infancy probably do not change risk of eczema by one to two years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; moderate-certainty evidence; 3075 participants, 7 trials) nor time to onset of eczema (hazard ratio 0.86, 95% CI 0.65 to 1.14; moderate-certainty evidence; 3349 participants, 9 trials). It is unclear whether skin care interventions during infancy change risk of IgE-mediated food allergy by one to two years of age (RR 2.53, 95% CI 0.99 to 6.47; 996 participants, 1 trial) or allergic sensitisation to a food allergen at age one to two years (RR 0.86, 95% CI 0.28 to 2.69; 1055 participants, 2 trials) due to very low-certainty evidence for these outcomes. Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low-certainty evidence; 1171 participants, 1 trial). However, this was only seen for cow's milk, and may be unreliable due to significant over-reporting of cow's milk allergy in infants. Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.34, 95% CI 1.02 to 1.77; moderate-certainty evidence; 2728 participants, 6 trials) and may increase risk of infant slippage over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low-certainty evidence; 2538 participants, 4 trials) or stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low-certainty evidence; 343 participants, 4 trials), although confidence intervals for slippages and stinging/allergic reactions are wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses show that effects of interventions were not influenced by age, duration of intervention, hereditary risk, FLG mutation, or classification of intervention type for risk of developing eczema. We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and risk of developing eczema or food allergy.
AUTHORS' CONCLUSIONS
Skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema, and probably increase risk of skin infection. Effects of skin care interventions on risk of food allergy are uncertain. Further work is needed to understand whether different approaches to infant skin care might promote or prevent eczema and to evaluate effects on food allergy based on robust outcome assessments.
Topics: Bias; Eczema; Emollients; Female; Filaggrin Proteins; Food Hypersensitivity; Humans; Hypersensitivity, Immediate; Immunoglobulin E; Infant; Infant, Newborn; Male; Milk Hypersensitivity; Skin Care; Skin Diseases, Infectious; Soaps
PubMed: 33545739
DOI: 10.1002/14651858.CD013534.pub2 -
Journal of Cellular and Molecular... Jan 2021Cholangiocarcinoma (CCA) is a biliary epithelial tumour that can emerge at any point in the biliary tree. It is commonly classified based on its anatomical site of...
Cholangiocarcinoma (CCA) is a biliary epithelial tumour that can emerge at any point in the biliary tree. It is commonly classified based on its anatomical site of development into intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (PCC) and distal cholangiocarcinoma (DCC), each of which is associated with varying patient demographics, molecular characteristics and treatment options. CCA patients have poor overall prognoses and 5-year survival rates. Additionally, CCA is often diagnosed at an advanced stage, with surgical treatment restricted to early-stage disease. Owing to an increase in the incidence of ICC, that of CCA is also on the rise, with a corresponding increase in the associated mortality, particularly in South America and Asia. Therefore, the development of an effective treatment is crucial to improve the survival of CCA patients. We aimed to systematically review the current understanding of advanced CCA treatment and discuss potential effective strategies.
Topics: Animals; Cholangiocarcinoma; Humans; Klatskin Tumor; Models, Biological; Mutation; Radiotherapy; Receptor, Fibroblast Growth Factor, Type 2; Vascular Endothelial Growth Factor A
PubMed: 33277810
DOI: 10.1111/jcmm.16151