NextDenovo: an efficient error correction and accurate assembly tool for noisy long reads.

Long-read sequencing data, particularly those derived from the Oxford Nanopore sequencing platform, tend to exhibit high error rates. Here, we present NextDenovo, an efficient error correction and assembly tool for noisy long reads, which achieves a high level of accuracy in genome assembly. We apply NextDenovo to assemble 35 diverse human genomes from around the world using Nanopore long-read data. These genomes allow us to identify the landscape of segmental duplication and gene copy number variation in modern human populations. The use of NextDenovo should pave the way for population-scale long-read assembly using Nanopore long-read data.

Reducing health disparities in endometrial cancer care in 2024.

PURPOSE OF REVIEW: To summarize the most recent publications explaining disparities among patients diagnosed with endometrial cancer and identify areas of improvement. RECENT FINDINGS: Racial disparities in endometrial cancer care have been identified along the cancer continuum including risk, diagnosis, access to treatment, and overall survival. The mortality gap in endometrial cancer is one of the top five widest Black-White mortality gaps among all cancer diagnoses in the United States. Many publications have demonstrated that the disparities exist, the aim of this review is to identify actionable areas of improvement. To mitigate racial disparities, we must acknowledge that Black patients are at higher risk of high-risk subtypes of endometrial cancer, and their presentation can vary from what is considered typical for the most common type of endometrial cancer. We must address that practice recommendations for diagnosis may not be generalizable to all races and ethnicities, and that racism has an impact on how providers approach a work-up for Black vs. White patients. Finally, we must improve access to appropriate treatment by steadfastly adhering to recommended practice guidelines regardless of race/ethnicity and improving efforts to enroll a diverse patient population to clinical trials. SUMMARY: In this review, we sought to identify specific and actionable areas of improvement to reduce racial disparities in endometrial cancer care.

TP53 mutation and abnormal p53 expression in endometrial cancer: Associations with race and outcomes.

OBJECTIVE: This multi-center cohort study assessed associations between race, TP53 mutations, p53 expression, and histology to investigate racial survival disparities in endometrial cancer (EC). METHODS: Black and White patients with advanced or recurrent EC with Next Generation Sequencing data in the Endometrial Cancer Molecularly Targeted Therapy Consortium database were identified. Clinicopathologic and treatment variables were summarized by race and compared. Overall survival (OS) and progression-free survival (PFS) among all patients were estimated by the Kaplan-Meier method. Cox proportional hazards models estimated the association between race, TP53 status, p53 expression, histology, and survival outcomes. RESULTS: Black patients were more likely than White patients to have TP53-mutated (N = 727, 71.7% vs 49.7%, p < 0.001) and p53-abnormal (N = 362, 71.1% vs 53.2%, p = 0.003) EC. Patients with TP53-mutated EC had worse PFS (HR 2.73 (95% CI 1.88-3.97)) and OS (HR 2.20 (95% CI 1.77-2.74)) compared to those with TP53-wildtype EC. Patients with p53-abnormal EC had worse PFS (HR 2.01 (95% CI 1.22-3.32)) and OS (HR 1.61 (95% CI 1.18-2.19)) compared to those with p53-wildtype EC. After adjusting for TP53 mutation and p53 expression, race was not associated with survival outcomes. The most frequent TP53 variants were at nucleotide positions R273 (n = 54), R248 (n = 38), and R175 (n = 23), rates of which did not differ by race. CONCLUSIONS: Black patients are more likely to have TP53-mutated and p53-abnormal EC, which are associated with worse survival outcomes than TP53- and p53-wildtype EC. The higher frequency of these subtypes among Black patients may contribute to survival disparities.

Population structure and evolutionary history of the greater cane rat (Thryonomys swinderianus) from the Guinean Forests of West Africa.

Grasscutter (Thryonomys swinderianus) is a large-body old world rodent found in sub-Saharan Africa. The body size and the unique taste of the meat of this major crop pest have made it a target of intense hunting and a potential consideration as a micro-livestock. However, there is insufficient knowledge on the genetic diversity of its populations across African Guinean forests. Herein, we investigated the genetic diversity, population structures and evolutionary history of seven Nigerian wild grasscutter populations together with individuals from Cameroon, Republic of Benin, and Ghana, using five mitochondrial fragments, including D-loop and cytochrome b (CYTB). D-loop haplotype diversity ranged from 0.571 (± 0.149) in Republic of Benin to 0.921 (± 0.013) in Ghana. Within Nigeria, the haplotype diversity ranged from 0.659 (± 0.059) in Cross River to 0.837 (± 0.075) in Ondo subpopulation. The fixation index (FST), haplotype frequency distribution and analysis of molecular variance revealed varying levels of population structures across populations. No significant signature of population contraction was detected in the grasscutter populations. Evolutionary analyses of CYTB suggests that South African population might have diverged from other populations about 6.1 (2.6-10.18, 95% CI) MYA. Taken together, this study reveals the population status and evolutionary history of grasscutter populations in the region.

African Suid Genomes Provide Insights into the Local Adaptation to Diverse African Environments.

African wild suids consist of several endemic species that represent ancient members of the family Suidae and have colonized diverse habitats on the African continent. However, limited genomic resources for African wild suids hinder our understanding of their evolution and genetic diversity. In this study, we assembled high-quality genomes of a common warthog (Phacochoerus africanus), a red river hog (Potamochoerus porcus), as well as an East Asian Diannan small-ear pig (Sus scrofa). Phylogenetic analysis showed that common warthog and red river hog diverged from their common ancestor around the Miocene/Pliocene boundary, putatively predating their entry into Africa. We detected species-specific selective signals associated with sensory perception and interferon signaling pathways in common warthog and red river hog, respectively, which contributed to their local adaptation to savannah and tropical rainforest environments, respectively. The structural variation and evolving signals in genes involved in T-cell immunity, viral infection, and lymphoid development were identified in their ancestral lineage. Our results provide new insights into the evolutionary histories and divergent genetic adaptations of African suids.

Impact of treatment modality on pelvic floor dysfunction among uterine cancer survivors.

OBJECTIVE: Pelvic floor dysfunction is a common adverse effect of uterine cancer treatment. In this study we compared patient-reported outcomes regarding pelvic floor dysfunction among uterine cancer survivors after hysterectomy and bilateral salpingo-oophorectomy, surgery and brachytherapy, or surgery and external beam radiotherapy with or without brachytherapy versus women who had a hysterectomy for benign indications. METHODS: We used the validated 20-item Pelvic Floor Distress Inventory to assess lower urinary distress, colorectal distress, and pelvic organ prolapse dysfunction in each treatment group. Pelvic floor dysfunction-related quality of life in these domains was compared across treatment modalities using the Pelvic Floor Impact Questionnaire-7. Treatment type, body mass index, comorbidities, and number of vaginal births were obtained from medical records. A zero-inflated negative binomial regression model was used to assess the association of treatment regimens and covariates relative to the non-cancer cohort. RESULTS: A total of 309 surveys were analyzed. The median age of the patients at surgery was 58 years (range 20-87) and the median age at survey completion was 66 years (range 34-92). Most participants reported experiencing at least one symptom of pelvic floor dysfunction (76% by Pelvic Floor Distress Inventory-2). The type of treatment had no effect on overall pelvic floor dysfunction on multivariate analysis (all p>0.05). Worse urinary-related symptoms were associated with higher body mass index at surgery (OR 1.41), higher age at time of survey (OR 1.07), and higher numbers of vaginal births (OR 1.43) (all p<0.05). CONCLUSIONS: Overall, pelvic floor dysfunction did not significantly vary by treatment modality. Our findings suggest complex interactions among age, body mass index, and parity as to how uterine cancer treatment affects pelvic floor quality of life, which should be considered in the choice of treatment strategy and patient counseling.

Incidence and Survival of Multiple Primary Cancers in US Women With a Gynecologic Cancer.

Objectives: To evaluate risk of a second cancer and associated survival times in United States women with diagnosis of cancer. Methods: The Surveillance Epidemiology and End Results (SEER) database was queried for 2 cohorts of women aged 18 - 89 with either an index gynecologic or non-gynecologic cancer diagnosed between 1992 - 2017. Index cases were followed to determine if a second primary cancer was subsequently diagnosed; defined according to SEER multiple primary and histology coding rules. Standard Incident Ratios (SIR) and latency intervals between index diagnosis and second primary diagnosis were evaluated. Among those who developed a second primary cancer, median survival times from diagnosis of second primary cancer were also calculated. Results: Between 1992 - 2017, 227,313 US women were diagnosed with an index gynecological cancer and 1,483,016 were diagnosed with an index non-gynecologic cancer. Among patients with index gynecologic cancer, 7.78% developed a non-gynecologic subsequent primary cancer. The risk of developing any non-gynecologic cancer following an index gynecologic cancer was higher than the risk in the general population (SIR 1.05, 95% CI 1.04 - 1.07). Organs especially at risk were Thyroid (SIR 1.45), Colon and Rectum (SIR 1.23), and Urinary System (SIR 1.33). Among women diagnosed with an index non-gynecologic cancer, 0.99% were diagnosed with a subsequent gynecologic cancer. The risk of developing a gynecologic cancer following a non-gynecologic cancer was also elevated compared to the average risk of the general population (SIR 1.05, 1.03 - 1.07), with uterine cancer having the highest SIR of 1.13. Conclusion: The risk of a developing a second primary cancer and the corresponding survival time is based on the order and site of the index and subsequent cancer. Surveillance guidelines should be examined further to optimize survivorship programs.

Tubal factor infertility and its impact on reproductive freedom of African American women.

In the past, the reproductive freedom of African American women was hindered by forced reproduction and sterilization campaigns. Unfortunately, these involuntary practices have now mostly been replaced by inequality because of disproportionate tubal factor infertility rates within African American communities. Our work aimed to describe the inequities in increased rates of pelvic inflammatory disease and tubal factor infertility as it relates to African American women. In addition, we highlighted the need for improved access to screening and treatment of sexually transmitted infections, access to barrier contraception, and health literacy related to the understanding and prevention of tubal factor infertility in African American women.

Massive ovarian edema masquerading as an androgen-secreting tumor.

OBJECTIVE: To highlight the management of massive ovarian edema in young reproductive-age women. DESIGN: A case report of a healthy female with clitoromegaly and elevated androgen levels secondary to massive ovarian edema. SETTING: Reproductive Endocrinology and Infertility Department of an academic hospital. PATIENT: A healthy 20-year-old woman who presented for routine gynecological care and was found to have a 2-cm clitoromegaly and elevated androgen levels. INTERVENTIONS: The patient underwent a diagnostic laparoscopy and right oophorectomy. MAIN OUTCOME MEASURES: Measurement of androgen levels. RESULTS: Final pathology showed massive edema of the ovary with no evidence of malignancy or androgen-secreting tumor cells. In addition, resolution of the elevated androgen levels was observed. CONCLUSIONS: Massive ovarian edema due to asymptomatic subacute torsion should be included in the differential diagnosis of reproductive-age patients who present with ovarian mass and hyperandrogenemia within the tumor range. Although not performed in our case, conservative management that involves detorsion, ovarian biopsy, and oophoropexy to prevent a recurrence should be the treatment of choice.

Regulatory network of miRNA, lncRNA, transcription factor and target immune response genes in bovine mastitis.

Pre- and post-transcriptional modifications of gene expression are emerging as foci of disease studies, with some studies revealing the importance of non-coding transcripts, like long non-coding RNAs (lncRNAs) and microRNAs (miRNAs). We hypothesize that transcription factors (TFs), lncRNAs and miRNAs modulate immune response in bovine mastitis and could potentially serve as disease biomarkers and/or drug targets. With computational analyses, we identified candidate genes potentially regulated by miRNAs and lncRNAs base pair complementation and thermodynamic stability of binding regions. Remarkably, we found six miRNAs, two being bta-miR-223 and bta-miR-24-3p, to bind to several targets. LncRNAs NONBTAT027932.1 and XR_003029725.1, were identified to target several genes. Functional and pathway analyses revealed lipopolysaccharide-mediated signaling pathway, regulation of chemokine (C-X-C motif) ligand 2 production and regulation of IL-23 production among others. The overarching interactome deserves further in vitro/in vivo explication for specific molecular regulatory mechanisms during bovine mastitis immune response and could lay the foundation for development of disease markers and therapeutic intervention.

Pulmonary metastasis as a primary manifestation of gestational choriocarcinoma in a third trimester pregnancy.

•Choriocarcinomas can follow molar, ectopic, or normal pregnancies.•The early diagnosis and treatment of choriocarcinomas is imperative.•Atypical symptoms in pregnancy should raise suspicion for choriocarcinoma.•Choriocarcinoma must always be in the differential in uncomplicated term pregnancies.

Hysteroscopic Morcellation in Endometrial Cancer Diagnosis: Increased Risk?

STUDY OBJECTIVE: Operative hysteroscopy requires elevated intrauterine pressures, which could lead to the spread of malignant cells into the peritoneal cavity. Currently, there is a paucity of data analyzing clinical outcomes in endometrial cancer after hysteroscopic morcellation with newer equipment. In this study, we sought to determine whether there are increased rates of positive peritoneal cytology, lymphovascular space invasion, or surgical upstaging in patients undergoing hysteroscopic morcellation compared with alternative endometrial biopsy methods. DESIGN: A retrospective chart review of patients from 2013-2018 was performed. The exclusion criteria included biopsy at outside institution, stage IV endometrial cancer known before biopsy, and missing data regarding biopsy method and histology. Peritoneal cytology results, lymphovascular space invasion, and surgical staging were compared by method of biopsy and histology using chi-square and Kruskal-Wallis tests. SETTING: The patients included in this study were accrued from the Karmanos Cancer Insittute in Detroit, Michigan. PATIENTS: A total of 289 patients met the inclusion criteria: 184 patients were classified as low-grade (Fédération Internationale de Gynécologie et d'Obstétrique grades 1 and 2) and 105 as high-grade (Fédération Internationale de Gynécologie et d'Obstétrique grade 3, serous, clear cell, and carcinosarcoma) endometrial cancer. INTERVENTIONS: Fifty-three patients (18%) underwent hysteroscopy with morcellation. Alternative biopsy methods included hysteroscopy without morcellation, n = 81 (28%); endometrial biopsy, n = 112 (38.7%); and dilation and curettage, n = 43 (15%). MEASUREMENTS AND MAIN RESULTS: Positive peritoneal cytology was noted in 34 cases (12%) and negative cytology in 165 (57%). Cytology was not performed in 90 cases (31%). When comparing outcomes by histologic subtypes, no difference was seen in peritoneal cytology (p = .704 and .727 for low grade and high grade, respectively), stage (p = .773 and .053 for low grade and high grade, respectively) or lymphovascular space invasion (p = .400 and .142 for low grade and high grade, respectively). CONCLUSION: Our study demonstrates that hysteroscopy with morcellation is a safe diagnostic method for low- and high-grade endometrial pathologic conditions and does not lead to increased dissemination of malignant cells, lymphovascular space invasion, or upstaging of patients.

Population Genomics Reveals Incipient Speciation, Introgression, and Adaptation in the African Mona Monkey (Cercopithecus mona).

Guenons (tribe Cercopithecini) are the most widely distributed nonhuman primate in the tropical forest belt of Africa and show considerable phenotypic, taxonomic, and ecological diversity. However, genomic information for most species within this group is still lacking. Here, we present a high-quality de novo genome (total 2.90 Gb, contig N50 equal to 22.7 Mb) of the mona monkey (Cercopithecus mona), together with genome resequencing data of 13 individuals sampled across Nigeria. Our results showed differentiation between populations from East and West of the Niger River ∼84 ka and potential ancient introgression in the East population from other mona group species. The PTPRK, FRAS1, BNC2, and EDN3 genes related to pigmentation displayed signals of introgression in the East population. Genomic scans suggest that immunity genes such as AKT3 and IL13 (possibly involved in simian immunodeficiency virus defense), and G6PD, a gene involved in malaria resistance, are under positive natural selection. Our study gives insights into differentiation, natural selection, and introgression in guenons.

DNA barcoding and species delimitation of butterflies (Lepidoptera) from Nigeria.

Accurate identification of species is a prerequisite for successful biodiversity management and further genetic studies. Species identification techniques often require both morphological diagnostics and molecular tools, such as DNA barcoding, for correct identification. In particular, the use of the subunit I of the mitochondrial cytochrome c oxidase (COI) gene for DNA barcoding has proven useful in species identification for insects. However, to date, no studies have been carried out on the DNA barcoding of Nigerian butterflies. We evaluated the utility of DNA barcoding applied for the first time to 735 butterfly specimens from southern Nigeria. In total, 699 DNA barcodes, resulting in a record of 116 species belonging to 57 genera, were generated. Our study sample comprised 807 DNA barcodes based on sequences generated from our current study and 108 others retrieved from BOLD. Different molecular analyses, including genetic distance-based evaluation (Neighbor-Joining, Maximum Likelihood and Bayesian trees) and species delimitation tests (TaxonDNA, Automated Barcode Gap Discovery, General Mixed Yule-Coalescent, and Bayesian Poisson Tree Processes) were performed to accurately identify and delineate species. The genetic distance-based analyses resulted in 163 well-separated clusters consisting of 147 described and 16 unidentified species. Our findings indicate that about 90.20% of the butterfly species were explicitly discriminated using DNA barcodes. Also, our field collections reported the first country records of ten butterfly species-Acraea serena, Amauris cf. dannfelti, Aterica galena extensa, Axione tjoane rubescens, Charaxes galleyanus, Papilio lormieri lormeri, Pentila alba, Precis actia, Precis tugela, and Tagiades flesus. Further, DNA barcodes revealed a high mitochondrial intraspecific divergence of more than 3% in Bicyclus vulgaris vulgaris and Colotis evagore. Furthermore, our result revealed an overall high haplotype (gene) diversity (0.9764), suggesting that DNA barcoding can provide information at a population level for Nigerian butterflies. The present study confirms the efficiency of DNA barcoding for identifying butterflies from Nigeria. To gain a better understanding of regional variation in DNA barcodes of this biogeographically complex area, future work should expand the DNA barcode reference library to include all butterfly species from Nigeria as well as surrounding countries. Also, further studies, involving relevant genetic and eco-morphological datasets, are required to understand processes governing mitochondrial intraspecific divergences reported in some species complexes.

DNA Barcoding Silver Butter Catfish (Schilbe intermedius) Reveals Patterns of Mitochondrial Genetic Diversity Across African River Systems.

The silver butter catfish (Schilbe intermedius) is widely distributed across African river systems. To date, information on its mitochondrial genetic diversity, population structure, and historical demography are not well-established. Herein, we combined newly generated mitochondrial cytochrome c oxidase (COI) subunit I gene sequences with previously published COI sequences in the global databases to reconstruct its phylogeography, population genetic structure, and historical demography. Results from the mtDNA phylogeography and species delimitation tests (Cluster algorithm - Species Identifier, Automatic Barcode Gap Discovery and Poison Tree Process model) revealed that S. intermedius comprises at least seven geographically defined matrilines. Although the overall haplotype diversity of S. intermedius was high (h = 0.90), results showed that East (Kenya) and West (Nigeria) African populations had low levels of haplotype diversity (h = ~0.40). In addition, population genetic polymorphism and historical demographics showed that S. intermedius populations in both East and West Africa underwent severe contractions as a result of biogeographic influences. The patterns of genetic diversity and population structure were consistent with adaptive responses to historical biogeographic factors and contemporary environmental variations across African river systems. This is suggestive of the influence of historical biogeographic factors and climatic conditions on population divergence of S. intermedius across African river systems. Given our discovery of previously underappreciated diversity within S. intermedius, we recommend that this species be considered for increased conservation and management.

Genomic and Phenotypic Analyses Reveal Mechanisms Underlying Homing Ability in Pigeon.

The homing pigeon was selectively bred from the domestic pigeon for a homing ability over long distances, a very fascinating but complex behavioral trait. Here, we generate a total of 95 whole genomes from diverse pigeon breeds. Comparing the genomes from the homing pigeon population with those from other breeds identifies candidate positively selected genes, including many genes involved in the central nervous system, particularly spatial learning and memory such as LRP8. Expression profiling reveals many neuronal genes displaying differential expression in the hippocampus, which is the key organ for memory and navigation and exhibits significantly larger size in the homing pigeon. In addition, we uncover a candidate gene GSR (encoding glutathione-disulfide reductase) experiencing positive selection in the homing pigeon. Expression profiling finds that GSR is highly expressed in the wattle and visual pigment cell layer, and displays increased expression levels in the homing pigeon. In vitro, a magnetic field stimulates increases in calcium ion concentration in cells expressing pigeon GSR. These findings support the importance of the hippocampus (functioning in spatial memory and navigation) for homing ability, and the potential involvement of GSR in pigeon magnetoreception.

Survival and late toxicities following concurrent chemo-radiotherapy for locally advanced stage III non-small cell lung cancer: findings of a 10-year Australian single centre experience with long term clinical follow up.

BACKGROUND: The preferred management of patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemo-radiotherapy (CRT). Acute CRT-related toxicities are well defined, however, less is known about late toxicities. The aim of the study was to examine the outcomes and late toxicities in Stage III NSCLC treated with CRT. METHODS: A retrospective review of the data from patients with stage III NSCLC treated with CRT was performed between May 2000 and June 2010. Demographics, tumour and treatment characteristics, toxicities and survival data were examined from hospital records of the patients. Progression free survival (PFS) and overall survival (OS) were evaluated by standard Kaplan-Meier survival curves. The censor date was set on 31 October 2016. RESULTS: Sixty-three patients were identified with a median age of 66.6 years [interquartile range (IQR) 57.2-72.1], two-third (n=41, 65.1%) were male, majority were current or ex-smokers (n=52, 82.5%), 42 (66.7%) patients had stage IIIB disease and 21 (33.3%) had stage IIIA disease. The most common histologic subtype was adenocarcinoma 30 (47.6%). The median PFS and OS of the whole population was 10.6 months (95% CI, 4.1-17.3 months) and 21 months (95% CI, 12.7-29.3 months) respectively. The 5-year OS rates for stage IIIA and IIIB were 24% and 16% respectively. The 1-, 3- and 5-year OS rates for all patients were 63.5%, 46% and 18.7% respectively. Acute grade 3 and 4 toxicities included 28 haematological and 17 non-haematological events. The incidence of late toxicities was 58.9%. Thirty-three events of late grade 3 and 4 toxicities were recorded. The most common late toxicity was symptomatic radiation-induced pulmonary fibrosis (39.3%), others include ototoxicity (7.1%), persistent dysphagia (7.1%) and one case of acute myeloid leukaemia. All patients that were alive at the censor date had developed radiation-induced fibrosis with associated symptoms of respiratory insufficiency. CONCLUSIONS: The 5-year OS of patients with stage III NSCLC treated with CRT was in keeping with survival figures reported from prospective clinical trials. There is, however, significant morbidity associated with long-term survival and this should be taken into account when making informed treatment decisions.

Conserved sequences identify the closest living relatives of primates.

Elucidating the closest living relatives of extant primates is essential for fully understanding important biological processes related to the genomic and phenotypic evolution of primates, especially of humans. However, the phylogenetic placement of these primate relatives remains controversial, with three primary hypotheses currently espoused based on morphological and molecular evidence. In the present study, we used two algorithms to analyze differently partitioned genomic datasets consisting of 45.4 Mb of conserved non-coding elements and 393 kb of concatenated coding sequences to test these hypotheses. We assessed different genomic histories and compared with other molecular studies found solid support for colugos being the closest living relatives of primates. Our phylogeny showed Cercopithecinae to have low levels of nucleotide divergence, especially for Papionini, and gibbons to have a high rate of divergence. The MCMCtree comprehensively updated divergence dates of early evolution of Primatomorpha and Primates.