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The objective of this systematic review and meta-analyses is to estimate the prevalence of long-COVID in children and adolescents and to present the full spectrum of symptoms present after acute COVID-19. We have used PubMed and Embase to identify observational studies published before February 10th, 2022 that included a minimum of 30 patients with ages ranging from 0 to 18 years that met the National Institute for Healthcare Excellence (NICE) definition of long-COVID, which consists of both ongoing (4 to 12 weeks) and post-COVID-19 (≥ 12 weeks) symptoms. Random-effects meta-analyses were performed using the MetaXL software to estimate the pooled prevalence with a 95% confidence interval (CI). Heterogeneity was assessed using I2 statistics. The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed (registration PROSPERO CRD42021275408). The literature search yielded 8373 publications, of which 21 studies met the inclusion criteria, and a total of 80,071 children and adolescents were included. The prevalence of long-COVID was 25.24%, and the most prevalent clinical manifestations were mood symptoms (16.50%), fatigue (9.66%), and sleep disorders (8.42%). Children infected by SARS-CoV-2 had a higher risk of persistent dyspnea, anosmia/ageusia, and/or fever compared to controls. Limitations of the studies analyzed include lack of standardized definitions, recall, selection, misclassification, nonresponse and/or loss of follow-up, and a high level of heterogeneity. [ABSTRACT FROM AUTHOR]

PURPOSE: Previous studies have shown an approximately two-fold elevation in the relative risk of urinary bladder cancer (UBC) among people with a family history that could not be entirely explained by shared environmental exposures, thus suggesting a genetic component in its predisposition. Multiple genome-wide association studies and recent gene panel sequencing studies identified several genetic loci that are associated with UBC risk; however, the list of UBC-associated variants and genes is incomplete. MATERIALS AND METHODS: We exome sequenced eight patients from three multiplex UBC pedigrees and a group of 77 unrelated familial UBC cases matched to 241 cancer-free controls. In addition, we examined pathogenic germline variation in 444 candidate genes in 392 The Cancer Genome Atlas UBC cases. RESULTS: In the pedigrees, segregating variants were family-specific although the identified genes clustered in common pathways, most notably DNA repair (MLH1 and MSH2) and cellular metabolism (IDH1 and ME1). In the familial UBC group, the proportion of pathogenic and likely pathogenic variants was significantly higher in cases compared with controls (P =.003). Pathogenic and likely pathogenic variant load was also significantly increased in genes involved in cilia biogenesis (P =.001). In addition, a pathogenic variant in CHEK2 (NM_007194.4:c.1100del; p.T367Mfs*15) was over-represented in cases (variant frequency = 2.6%; 95% CI, 0.71 to 6.52) compared with controls (variant frequency = 0.21%; 95% CI, 0.01 to 1.15), but was not statistically significant. CONCLUSION: These results point to a complex polygenic predisposition to UBC. Despite heterogeneity, the genes cluster in several biologically relevant pathways and processes, for example, DNA repair, cilia biogenesis, and cellular metabolism. Larger studies are required to determine the importance of CHEK2 in UBC etiology. [ABSTRACT FROM AUTHOR]

COVID-19 can involve persistence, sequelae, and other medical complications that last weeks to months after initial recovery. This systematic review and meta-analysis aims to identify studies assessing the long-term effects of COVID-19. LitCOVID and Embase were searched to identify articles with original data published before the 1st of January 2021, with a minimum of 100 patients. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. PRISMA guidelines were followed. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included (age 17–87 years). The included studies defined long-COVID as ranging from 14 to 110 days post-viral infection. It was estimated that 80% of the infected patients with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). Multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care. [ABSTRACT FROM AUTHOR]

Introduction: Astrocytomas are the most common and aggressive primary brain tumors, and they are classified according to the degree of malignancy on a scale of I to IV, in which grade I is the least malignant and grade IV the highest. Many factors are related to astrocytomas progression as progesterone receptor (PR), whose transcriptional activity could be regulated by phosphorylation by protein kinase C alpha (PKCα) at the residue Ser400. Our aim was to investigate if PR phosphorylation together with PKCα expression could be used as a prognostic factor for astrocytomas malignancy. Methods: By immunofluorescence, we detected the content of PKCα, PR and its phosphorylation at Ser400 in 46 biopsies from Mexican patients with different astrocytoma malignancy grades; by bioinformatic tools using TCGA data, we evaluated the expression of PR and PKCα mRNA according to astrocytoma malignancy grades. For all statistical analyses, significance was p< 0.05. Results: We detected a positive correlation between the tumor grade and the content of PKCα, PR and its phosphorylation at Ser400, as well as the intracellular colocalization of these proteins. Interestingly, using an in silico assay, we found that the PR and PKCα expression at mRNA level has an inverse ratio with astrocytomas tumor grade. Discussion: These results indicate that PR and its phosphorylation at Ser400 site, as well as PKCα and their colocalization, could be considered as possible malignancy biomarkers for astrocytomas grades I–IV. [ABSTRACT FROM AUTHOR]

The inherited bone marrow failure syndromes ( IBMFS) typically present with significant cytopenias in at least one haematopoietic cell lineage that may progress to pancytopenia, and are associated with increased risk of cancer. Although the clinical features of the IBMFS are often diagnostic, variable disease penetrance and expressivity may result in diagnostic dilemmas. The discovery of the genetic aetiology of the IBMFS has been greatly facilitated by next-generation sequencing methods. This has advanced understanding of the underlying biology of the IBMFS and been essential in improving clinical management and genetic counselling for affected patients. Herein we review the clinical features, underlying biology, and new genomic discoveries in the IBMFS, including Fanconi anaemia, dyskeratosis congenita, Diamond Blackfan anaemia, Shwachman Diamond syndrome and some disorders of the myeloid and megakaryocytic lineages. [ABSTRACT FROM AUTHOR]

• This umbrella review summarizes the evidence of 16 years of research on the genetics of SUDs from more than 150 meta-analyses. • OPRM1, DRD2, DRD4, BDNF and SL6A4 genes are associated with two or more Substance use disorders. • Genes that had an OR higher than two were the SLC6A4 for all addictions, the ADH1B for alcohol dependence, and BDNF for methamphetamine dependence. • CHRNA5 gene has been identified in GWAS and candidate genes meta-analyses. Substance use disorders (SUD) are a category of psychiatric disorders with a large epidemiological and societal impact around the world. In the last decades, a large number of genetic studies have been published for SUDs. With the objective of having an overview and summarizing the evidence published up to date, we carried out an umbrella review of all the meta-analyses of genetic studies for the following substances: alcohol, tobacco, cannabis, cocaine, opioids, heroin and methamphetamines. Meta-analyses for candidate gene studies and genome-wide association studies (GWAS) were included. Alcohol and tobacco were the substances with the largest number of meta-analyses, and cannabis, opioids and cocaine the least studied. The following genes were associated with two or more SUDs: OPRM1, DRD2, DRD4, BDNF and SL6A4. The only genes that had an OR higher than two were the SLC6A4 for all addictions, the ADH1B for alcohol dependence, and BDNF for methamphetamine dependence. GWAS confirmed the possible role of CHRNA 5 gene in nicotine dependence and identified novel candidate genes in other SUDs, such as FOXP2 , PEX and , AUTS2 , which need further functional analyses. This umbrella review summarizes the evidence of 16 years of research on the genetics of SUDs and provides a broad and detailed overview of results from more than 150 meta-analyses for SUD. The results of this umbrella review will guide the need for future genetic studies geared toward understanding, preventing and treating SUDs. [ABSTRACT FROM AUTHOR]

The present review aimed to discuss contemporary scientific literature involving differences between the tumor microenvironment (TME) in melanoma, lung cancer, and breast cancer in their primary site and TME in brain metastases (BM). TME plays a fundamental role in the behavior of cancer. In the process of carcinogenesis, cells such as fibroblasts, macrophages, endothelial cells, natural killer cells, and other cells can perpetuate and progress carcinogenesis via the secretion of molecules. Oxygen concentration, growth factors, and receptors in TME initiate angiogenesis and are examples of the importance of microenvironmental conditions in the performance of neoplastic cells. The most frequent malignant brain tumors are metastatic in origin and primarily originate from lung cancer, breast cancer, and melanoma. Metastatic cancer cells have to adhere to and penetrate the blood-brain barrier (BBB). After traversing BBB, these cells have to survive by producing various cytokines, chemokines, and mediators to modify their new TME. The microenvironment of these metastases is currently being studied owing to the discovery of new therapeutic targets. In these three types of tumors, treatment is more effective in the primary tumor than in BM due to several factors, including BBB. Understanding the differences in the characteristics of the microenvironment surrounding the primary tumor and their respective metastasis might help improve strategies to comprehend cancer. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS) is the main hereditary colorectal cancer syndrome. There have been few reports regarding the clinical and molecular characteristics of LS patients in Latin America; this is particularly true in the Mexican population, where no information is available. The present study aims to describe the clinical and molecular spectrum of variants in a cohort of patients diagnosed with LS in Mexico. We present a retrospective analysis of 412 patients with suspected LS, whose main site of cancer diagnosis was the colon (58.25%), followed by the endometrium (18.93%). Next-generation sequencing analysis, with an extensive multigene panel, showed that 27.1% (112/414) had a variant in one of the genes of the mismatch repair pathway (MMR); 30.4% (126/414) had a variant in non-MMR genes such as CHEK2, APC, MUTYH, BRCA1, and BRCA2; and 42.5% (176/414) had no genetic variants. Most of the variants were found in MLH1. Pathogenic variants (PVs) in MMR genes were identified in 65.7% (96/146) of the total PVs, and 34.24% (45/146) were in non-MMR genes. Molecular and clinical characterization of patients with LS in specific populations allowed personalized follow-up, with the option for targeted treatment with immune checkpoint inhibitors and the development of public health policies. Moreover, such characterization allows for family cascade testing and consequent prevention strategies. [ABSTRACT FROM AUTHOR]

Benign tumors that grow in the spinal canal are heterogeneous neoplasms with low incidence; from these, meningiomas and nerve sheath tumors (neurofibromas and schwannomas) account for 60%–70% of all primary spinal tumors. Benign spinal canal tumors provoke nonspecific clinical manifestations, mostly related to the affected level of the spinal cord. These tumors present a challenge for the patient and healthcare professionals, for they are often difficult to diagnose and the high frequency of posttreatment complications. In this review, we describe the epidemiology, risk factors, clinical features, diagnosis, histopathology, molecular biology, and treatment of extramedullary benign meningiomas, osteoid osteomas, osteoblastomas, aneurysmal bone cysts, osteochondromas, neurofibromas, giant cell tumors of the bone, eosinophilic granulomas, hemangiomas, lipomas, and schwannomas located in the spine, as well as possible future targets that could lead to an improvement in their management. [ABSTRACT FROM AUTHOR]

Background: Li-Fraumeni syndrome, caused primarily by pathogenic or likely pathogenic germline TP53 variants, is a rare, variably penetrant, cancer predisposition syndrome with very high risks of cancer starting in childhood, including the risk of multiple primary malignancies over an individual's lifespan. We aimed to characterise and quantify cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants.Methods: This observational cohort study was done in 480 carriers of pathogenic or likely pathogenic germline TP53 variants enrolled in the National Cancer Institute's referral-based longitudinal Li-Fraumeni syndrome study between Aug 1, 2011, and March 24, 2020. Data on personal and family history of cancer were obtained through study questionnaires and validated by medical records. Variants were categorised on the basis of both loss-of-function (LOF) and dominant-negative effect (DNE) properties. Cancer incidence associated with Li-Fraumeni syndrome was compared with that of the general population using the Surveillance, Epidemiology, and End Results (SEER) 1975-2017 registry. Cancer incidence was evaluated with family-clustered Cox regression models and competing risk methods. This study is registered with ClinicalTrials.gov, NCT01443468.Findings: Individuals with Li-Fraumeni syndrome had a nearly 24 times higher incidence of any cancer than the general population (standardised incidence ratio 23·9; 95% CI 21·9-26·0), with the highest comparative incidence from childhood to 30 years of age. The overall cancer incidence remained 10·3 (95% CI 7·9-13·2) times higher than that of the general population after age 50 years. In women, when considering breast cancer as a competing risk, the probability of a first diagnosis of a non-breast cancer malignancy was substantially lower than that of any first cancer (24·4% [95% CI 19·6-30·5] vs 50·4% [43·5-56·5] by age 33·7 years). Overall, DNE_LOF and notDNE_LOF variants were associated with earlier age at first and second cancer compared with notDNE_notLOF and DNE_notLOF variants. The time interval from first to second cancer was shorter among carriers whose first cancer diagnoses were later in life. Multiple cancers were diagnosed within a short timeframe in some individuals, regardless of the order of cancer occurrence.Interpretation: This study adds granularity to the understanding of cancer incidence and patterns in individuals with pathogenic or likely pathogenic germline TP53 variants. Integration of age range-specific cancer incidence estimates, cancer-free survival by functional variant group, the potential impact of risk-reducing mastectomy on female cancer incidence, and data on subsequent malignancies will be important for the development of strategies to optimise cancer screening and management for these individuals.Funding: Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Institutes of Health. [ABSTRACT FROM AUTHOR]

PURPOSE: Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and accounts for 3% of all pediatric cancer. In this study, we investigated germline sequence and structural variation in a broad set of genes in two large, independent RMS cohorts. MATERIALS AND METHODS: Genome sequencing of the discovery cohort (n = 273) and exome sequencing of the secondary cohort (n = 121) were conducted on germline DNA. Analyses were performed on 130 cancer susceptibility genes (CSG). Pathogenic or likely pathogenic (P/LP) variants were predicted using the American College of Medical Genetics and Genomics (ACMG) criteria. Structural variation and survival analyses were performed on the discovery cohort. RESULTS: We found that 6.6%-7.7% of patients with RMS harbored P/LP variants in dominant-acting CSG. An additional approximately 1% have structural variants (ATM , CDKN1C) in CSGs. CSG variants did not influence survival, although there was a significant correlation with an earlier age of tumor onset. There was a nonsignificant excess of P/LP variants in dominant inheritance genes in the patients with FOXO1 fusion–negative RMS patients versus the patients with FOXO1 fusion–positive RMS. We identified pathogenic germline variants in CSGs previously (TP53 , NF1 , DICER1 , mismatch repair genes), rarely (BRCA2 , CBL , CHEK2 , SMARCA4), or never (FGFR4) reported in RMS. Numerous genes (TP53 , BRCA2 , mismatch repair) were on the ACMG Secondary Findings 2.0 list. CONCLUSION: In two cohorts of patients with RMS, we identified pathogenic germline variants for which gene-specific therapies and surveillance guidelines may be beneficial. In families with a proband with an RMS-risk P/LP variant, genetic counseling and cascade testing should be considered, especially for ACMG Secondary Findings genes and/or with gene-specific surveillance guidelines. [ABSTRACT FROM AUTHOR]

PURPOSE: Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and accounts for 3% of all pediatric cancer. In this study, we investigated germline sequence and structural variation in a broad set of genes in two large, independent RMS cohorts. MATERIALS AND METHODS: Genome sequencing of the discovery cohort (n = 273) and exome sequencing of the secondary cohort (n = 121) were conducted on germline DNA. Analyses were performed on 130 cancer susceptibility genes (CSG). Pathogenic or likely pathogenic (P/LP) variants were predicted using the American College of Medical Genetics and Genomics (ACMG) criteria. Structural variation and survival analyses were performed on the discovery cohort. RESULTS: We found that 6.6%-7.7% of patients with RMS harbored P/LP variants in dominant-acting CSG. An additional approximately 1% have structural variants (ATM , CDKN1C) in CSGs. CSG variants did not influence survival, although there was a significant correlation with an earlier age of tumor onset. There was a nonsignificant excess of P/LP variants in dominant inheritance genes in the patients with FOXO1 fusion–negative RMS patients versus the patients with FOXO1 fusion–positive RMS. We identified pathogenic germline variants in CSGs previously (TP53 , NF1 , DICER1 , mismatch repair genes), rarely (BRCA2 , CBL , CHEK2 , SMARCA4), or never (FGFR4) reported in RMS. Numerous genes (TP53 , BRCA2 , mismatch repair) were on the ACMG Secondary Findings 2.0 list. CONCLUSION: In two cohorts of patients with RMS, we identified pathogenic germline variants for which gene-specific therapies and surveillance guidelines may be beneficial. In families with a proband with an RMS-risk P/LP variant, genetic counseling and cascade testing should be considered, especially for ACMG Secondary Findings genes and/or with gene-specific surveillance guidelines. [ABSTRACT FROM AUTHOR]

The angiotensin-converting enzyme 2 (ACE2) is the host functional receptor for the new virus SARS-CoV-2 causing Coronavirus Disease 2019. ACE2 is expressed in 72 different cell types. Some factors that can affect the expression of the ACE2 are: sex, environment, comorbidities, medications (e.g. anti-hypertensives) and its interaction with other genes of the renin-angiotensin system and other pathways. Different factors can affect the risk of infection of SARS-CoV-2 and determine the severity of the symptoms. The ACE2 enzyme is a negative regulator of RAS expressed in various organ systems. It is with immunity, inflammation, increased coagulopathy, and cardiovascular disease. In this review, we describe the genetic and molecular functions of the ACE2 receptor and its relation with the physiological and pathological conditions to better understand how this receptor is involved in the pathogenesis of COVID-19. In addition, it reviews the different comorbidities that interact with SARS-CoV-2 in which also ACE2 plays an important role. It also describes the different factors that interact with the virus that have an influence in the expression and functional activities of the receptor. The goal is to provide the reader with an understanding of the complexity and importance of this receptor. [ABSTRACT FROM AUTHOR]

The deletion of exons 9 to 12 of BRCA1 (9–12 del BRCA1) is considered a founder mutation in the Mexican population. We evaluate the usefulness of the target detection of 9–12 del BRCA1 as the first molecular diagnostic strategy in patients with Hereditary Breast and Ovarian Cancer (HBOC). We performed the genetic assessment of 637 patients with suspected HBOC. The region corresponding to the breakpoints for the 9–12 del BRCA1 was amplified by polymerase chain reaction (PCR). An analysis of the clinical data of the carriers and non-carriers was done, searching for characteristics that correlated with the deletion. The 9–12 del BRCA1 was detected in 5% of patients with suspected HBOC (30/637). In patients diagnosed with ovarian cancer, 13 of 30 were 9–12 del BRCA1 carriers, which represents 43%. We found a significant association between the 9–12 del BRCA1 carriers with triple negative breast cancer and high-grade papillary serous ovarian cancer. We concluded that the detection of the 9–12 del BRCA1 is useful as a first molecular diagnostic strategy in the Mexican population. In particular, it shortens the gap in genetic assessment in patients with triple negative breast cancer and ovarian cancer. [ABSTRACT FROM AUTHOR]

Introduction: Renin-angiotensin system (RAS) in brain cancer represents a scarcely explored field in neuro-oncology. Recently, some pre- and clinical studies have reported that RAS components play a relevant role in the development and behavior of gliomas. The angiotensinogen (AGT) rs5050 genetic variant has been identified as a crucial regulator of the transcription of AGT mRNA, which makes it a logical and promising target of research. The aim of this study was to determine the relationship between the AGT rs5050 genetic variant in blood with prognosis in astrocytoma. Methods: A prospective pilot study was performed on forty-eight astrocytoma patients, who received the standard-of-care treatment. Blood samples were taken prior to surgery and DNA was sequenced using Ion Torrent next-generation sequencing and analyzed by Ion Reporter software. Descriptive, bivariate, multivariate, and survival analyses were performed using SPSS v21, STATA 12 and GraphPad Prism 7. Results: Median follow-up was 41 months (range 1–48). Survival analysis showed a significant difference between the rs5050 genotypes (p = .05). We found lower survival rates in individuals with the GG-genotype of rs5050 AGT compared to patients with the TT- and TG-genotype (2 months vs. 11.5 months, respectively [p = .01]). In bivariate and multivariate analyses, GG-genotype was negatively associated with survival. Conclusions: In patients with astrocytoma, AGT rs5050 GG-genotype was associated with poor prognosis. We propose this germline genetic variant as a complementary biomarker, which can be detected practically and safely in blood samples or saliva. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) in young women, generally defined in oncology as women who are 40 years of age or younger, represents 2 out of 10 BC cases in developing countries. Several research studies, including genetic cancer panel tests, genome-wide association studies, expression analyses and polymorphisms reports, have found that young women with BC exhibit a higher genetic susceptibility and specific genomic signature compared to postmenopausal women with BC. Thus, international guidelines recommend genetic counseling for this age population. This review presents the current state of the art of genetics and genomics with regards to young women with BC. [ABSTRACT FROM AUTHOR]

Intracellular progesterone receptors (PRs) and protein kinases C (PKCs) are known regulators of cancer cell proliferation and metastasis. Both PRs and PKCs are found overexpressed in grade IV human astrocytomas, also known as glioblastomas, which are the most frequent and aggressive brain tumors. In the present study, we investigated whether PR activation by PKC induces the migration and invasion of glioblastoma derived cell lines and if PKCα and δ isoforms are involved in PR activation. We observed that PKC activation with tetradecanoylphorbol acetate (TPA) increases the migration and invasion capacity of two human glioblastoma derived human cell lines (U251 MG and U87) and that the treatment with the PR receptor antagonist RU486 blocks these processes. Interestingly, the pharmacological inhibition of the isoenzymes PKCα and PKCδ also resulted in a blocked PR transcriptional activity. Also, TPA-dependent PR activation increases the expression of progesterone-induced blocking factor (PIBF), a known PR target gene. These results hint to an existing cross-talk between PKCs and PRs in regulating the infiltration process of human glioblastomas. [ABSTRACT FROM AUTHOR]

Background: Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8–5%. We investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort (n = 1173) and in cancer-free ethnicity-matched controls (n = 982). Methods: We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS). Results: In the 24 genes on the ACMG SF v2.0 list associated with a cancer phenotype, we observed 8 P/LP unique variants (8 individuals; 0.8%) in controls and 11 P/LP unique variants (14 individuals; 1.2%) in cases, a non-significant difference. We reviewed 115 VUS. The median estimated per-variant review time required was 30 min; the first variant within a gene took significantly (p = 0.0009) longer to review (median = 60 min) compared with subsequent variants (median = 30 min). The concordance rate was 83.3% for the variants examined by two reviewers. Conclusion: The 115 VUS required database and literature review, a time- and labor-intensive process hampered by the difficulty in interpreting conflicting P/LP determinations. By rigorously investigating the 24 ACMG SF v2.0 cancer genes, our work establishes a benchmark P/LP variant prevalence rate in a familial cancer cohort and controls. [ABSTRACT FROM AUTHOR]

An abstract of the article "Epigenetic therapy with hydralazine and valproate associated to cisplatin chemoradiation in FIGO stage IIIB. A phase II study," by Myrna Candelaria, Lucely Cetina, and colleagues is presented.