Machine learning and bioinformatic analyses link the cell surface receptor transcript levels to the drug response of breast cancer cells and drug off-target effects.

Breast cancer responds variably to anticancer therapies, often leading to significant off-target effects. This study proposes that the variability in tumour responses and drug-induced adverse events is linked to the transcriptional profiles of cell surface receptors (CSRs) in breast tumours and normal tissues. We analysed multiple datasets to compare CSR expression in breast tumours with that in non-cancerous human tissues. Our findings correlate the drug responses of breast cancer cell lines with the expression levels of their targeted CSRs. Notably, we identified distinct differences in CSR expression between primary breast tumour subtypes and corresponding cell lines, which may influence drug response predictions. Additionally, we used clinical trial data to uncover associations between CSR gene expression in healthy tissues and the incidence of adverse drug reactions. This integrative approach facilitates the selection of optimal CSR targets for therapy, leveraging cell line dose-responses, CSR expression in normal tissues, and patient adverse event profiles.

Shedding light on the dark genome: Insights into the genetic, CRISPR-based, and pharmacological dependencies of human cancers and disease aggressiveness.

Investigating the human genome is vital for identifying risk factors and devising effective therapies to combat genetic disorders and cancer. Despite the extensive knowledge of the "light genome", the poorly understood "dark genome" remains understudied. In this study, we integrated data from 20,412 protein-coding genes in Pharos and 8,395 patient-derived tumours from The Cancer Genome Atlas (TCGA) to examine the genetic and pharmacological dependencies in human cancers and their treatment implications. We discovered that dark genes exhibited high mutation rates in certain cancers, similar to light genes. By combining the drug response profiles of cancer cells with cell fitness post-CRISPR-mediated gene knockout, we identified the crucial vulnerabilities associated with both dark and light genes. Our analysis also revealed that tumours harbouring dark gene mutations displayed worse overall and disease-free survival rates than those without such mutations. Furthermore, dark gene expression levels significantly influenced patient survival outcomes. Our findings demonstrated a similar distribution of genetic and pharmacological dependencies across the light and dark genomes, suggesting that targeting the dark genome holds promise for cancer treatment. This study underscores the need for ongoing research on the dark genome to better comprehend the underlying mechanisms of cancer and develop more effective therapies.

Mutational landscape of cancer-driver genes across human cancers.

The genetic mutations that contribute to the transformation of healthy cells into cancerous cells have been the subject of extensive research. The molecular aberrations that lead to cancer development are often characterised by gain-of-function or loss-of-function mutations in a variety of oncogenes and tumour suppressor genes. In this study, we investigate the genomic sequences of 20,331 primary tumours representing 41 distinct human cancer types to identify and catalogue the driver mutations present in 727 known cancer genes. Our findings reveal significant variations in the frequency of cancer gene mutations across different cancer types and highlight the frequent involvement of tumour suppressor genes (94%), oncogenes (93%), transcription factors (72%), kinases (64%), cell surface receptors (63%), and phosphatases (22%), in cancer. Additionally, our analysis reveals that cancer gene mutations are predominantly co-occurring rather than exclusive in all types of cancer. Notably, we discover that patients with tumours displaying different combinations of gene mutation patterns tend to exhibit variable survival outcomes. These findings provide new insights into the genetic landscape of cancer and bring us closer to a comprehensive understanding of the underlying mechanisms driving the development of various forms of cancer.

TBX3 Promotes Cervical Cancer Proliferation and Migration via HPV E6 and E7 Signaling.

Cervical cancer is a leading cause of cancer-related deaths in women globally and 99% of cases are caused by persistent infection with high-risk strains of the human papillomavirus (HPV). The HPV oncoproteins E6 and E7 establish the cancer phenotype by cooperating with host proteins and identifying them may have important therapeutic benefits. T-box transcription factor 3 (TBX3) is a critical developmental regulator, and when it is overexpressed postnatally, it contributes to several cancers, but little is known about its expression and role in cervical cancer. The current study shows that TBX3 is upregulated in cervical cancer cell lines as well as precancerous and cervical cancer patient tissue and is associated with larger and more invasive tumors. Knockdown and overexpression cell culture models show that TBX3 promotes HPV-positive cell proliferation, migration, and spheroid growth; however, TBX3 inhibits these processes in HPV-negative cells. Importantly, we show that the tumor promoting activity of TBX3 in cervical cancer is dependent on E6/E7. IMPLICATIONS: In summary, our study highlights the importance of TBX3 as a cooperating partner of E6/E7 in HPV-positive cervical cancer and identifies TBX3 as a potential therapeutic target to treat this neoplasm.

A genome-wide association study identifies distinct variants associated with pulmonary function among European and African ancestries from the UK Biobank.

Pulmonary function is an indicator of well-being, and pulmonary pathologies are the third major cause of death worldwide. We analysed the UK Biobank genome-wide association summary statistics of pulmonary function for Europeans and individuals of recent African descent to identify variants associated with the trait in the two ancestries. Here, we show 627 variants in Europeans and 3 in Africans associated with three pulmonary function parameters. In addition to the 110 variants in Europeans previously reported to be associated with phenotypes related to pulmonary function, we identify 279 novel loci, including an ISX intergenic variant rs369476290 on chromosome 22 in Africans. Remarkably, we find no shared variants among Africans and Europeans. Furthermore, enrichment analyses of variants separately for each ancestry background reveal significant enrichment for terms related to pulmonary phenotypes in Europeans but not Africans. Further analysis of studies of pulmonary phenotypes reveals that individuals of European background are disproportionally overrepresented in datasets compared to Africans, with the gap widening over the past five years. Our findings extend our understanding of the different variants that modify the pulmonary function in Africans and Europeans, a promising finding for future GWASs and medical studies.

Strongylopus grayii tadpole blastema extract exerts cytotoxic effects on embryonal rhabdomyosarcoma cells.

Amphibians have regenerative capacity and are resistant to developing cancer. This suggests that the developing blastema, located at the tissue regeneration site, may secrete anti-cancer factors. Here, we investigate the anti-cancer potential of tadpole tail blastema extracts (TAD) from the stream frog, Strongylopus grayii, in embryonal rhabdomyosarcoma (ERMS) cells. ERMS originates in skeletal muscle tissue and is a common pediatric soft tissue sarcoma. We show using MTT assays that TAD inhibited ERMS cell viability in a concentration-dependent manner, and phase contrast/fluorescent microscopy revealed that it induced morphological markers of senescence and apoptosis. Western blotting showed that this was associated with DNA damage (γH2AX) and activation of the p38/MAPK stress signaling pathway as well as molecular markers of senescence (p16INK4a), apoptosis (cleaved PARP), and inhibition of cell cycle promoters (cyclin A, CDK2, and cyclin B1). Furthermore, proteomics followed by gene ontology analyses showed that TAD treatment inhibited known tumor promoters and proteins required for cancer cell survival. Lastly, using the LINCS drug perturbation library, we show that there is an overlap between the proteomics signature induced by TAD and common anti-cancer drugs. Taken together, this study provides novel evidence that TAD exhibits cytotoxicity in ERMS cells.

The Effect of Contraception on Genital Cytokines in Women Randomized to Copper Intrauterine Device, Depot Medroxyprogesterone Acetate, or Levonorgestrel Implant.

BACKGROUND: The ECHO trial randomized women to intramuscular depot medroxyprogesterone acetate (DMPA-IM), levonorgestrel implant (LNG-implant), or copper intrauterine device (Cu-IUD). In a substudy of the ECHO trial, we tested the hypothesis that contraceptives influence genital inflammation by comparing cervicovaginal cytokine changes following contraception initiation. In addition, we compared cytokine profiles in women who acquired HIV (cases) versus those remaining HIV negative (controls). METHODS: Women (n = 251) from South Africa and Kenya were included. Twenty-seven cervicovaginal cytokines were measured by Luminex at baseline, and 1 and 6 months after contraceptive iTanko et alnitiation. In addition, cytokines were measured preseroconversion in HIV cases (n = 25) and controls (n = 100). RESULTS: At 6 months after contraceptive initiation, women using Cu-IUD had increased concentrations of 25/27 cytokines compared to their respective baseline concentrations. In contrast, women initiating DMPA-IM and LNG-implant did not experience changes in cervicovaginal cytokines. Preseroconversion concentrations of IL-1ß, IL-6, and TNF-α, previously associated with HIV risk, correlated with increased HIV risk in a logistic regression analysis, although not significantly after correcting for multiple comparisons. Adjusting for contraceptive arm did not alter these results. CONCLUSIONS: Although Cu-IUD use broadly increased cervicovaginal cytokine concentrations at 6 months postinsertion, these inflammatory changes were found not to be a significant driver of HIV risk. CLINICAL TRIALS REGISTRATION: NCT02550067.

Correlates of hypertension among persons living with HIV at Livingstone Central Hospital: A cross sectional study

Background: Persons living with HIV (PLWH) are more likely to develop hypertension and cardiovascular disease than the HIV-negative population. The new hypertension guidelines by the American Heart Association (AHA) and the American College of Cardiology (ACC) lowered the definition of hypertension from systolic and diastolic blood pressure (BP) of ≥ 140/90mmHg to ≥ 130/80, respectively. This study was aimed at determining the prevalence and factors associated with hypertension in PLWH in Livingstone using the new hypertension diagnostic criteria. Methods: This was a cross-sectional study. We recruited 226 antiretroviral treated PLWH attending routine visits. Socio-demographic, health and clinical data including BP readings were collected. Interviewer-structured questionnaires adapted from the World Health Organization Stepwise approach to Surveillance ( WHO STEPs) and the international physical activity questionnaire (IPAQ) were used to collect data. Statistical evaluations were employed to elucidate relationships between hypertension and all response variables. Results: The prevalence of hypertension using the old and new guidelines was 16% and 42%, respectively. Factors significantly associated with increased and reduced odds of developing hypertension after adjustments in multivariate logistic regression were age, body mass index (BMI), employment status, fasting blood sugar (FBS) and table salt consumption, respectively (p<0.05 for all). Using the new AHA/ACC criteria for hypertension shifted the prevalence from 16% (old criteria) to 42%.Conclusion: The prevalence of hypertension in PLH in Livingstone was 42% and the major risk factors associated with hypertension in PLWH were increasing age, BMI and FBS. We recommend the inclusion of FBS in routine measurements in PLWH. The AHA/ ACC new guidelines should be reenforced in low-cost settings to increase the treatment of hypertension among PLWH.

Targeting the oncogenic TBX3:nucleolin complex to treat multiple sarcoma subtypes.

Sarcomas are diverse cancers of mesenchymal origin, with compromised clinical management caused by insufficient diagnostic biomarkers and limited treatment options. The transcription factor TBX3 is upregulated in a diverse range of sarcoma subtypes, where it plays a direct oncogenic role, and it may thus represent a novel therapeutic target. To identify versatile ways to target TBX3, we performed affinity purification coupled by mass spectrometry to identify putative TBX3 protein cofactors that regulate its oncogenic activity in sarcomas. Here we identify and validate the multifunctional phosphoprotein nucleolin as a TBX3 cofactor. We show that nucleolin is co-expressed with TBX3 in several sarcoma subtypes and their expression levels positively correlate in sarcoma patients which are associated with poor prognosis. Furthermore, we demonstrate that nucleolin and TBX3 interact in chondrosarcoma, liposarcoma and rhabdomyosarcoma cells where they act together to enhance proliferation and migration and regulate a common set of tumor suppressor genes. Importantly, the nucleolin targeting aptamer, AS1411, exhibits selective anti-cancer activity in these cells and mislocalizes TBX3 and nucleolin to the cytoplasm which correlates with the re-expression of the TBX3/nucleolin target tumor suppressors CDKN1A (p21CIP1) and CDKN2A (p14ARF). Our findings provide the first evidence that TBX3 requires nucleolin to promote features of sarcomagenesis and that disruption of the oncogenic TBX3-nucleolin interaction by AS1411 may be a novel approach for treating sarcomas.

Proteogenomic analysis of pancreatic cancer subtypes.

Pancreatic cancer remains a significant public health problem with an ever-rising incidence of disease. Cancers of the pancreas are characterised by various molecular aberrations, including changes in the proteomics and genomics landscape of the tumour cells. Therefore, there is a need to identify the proteomic landscape of pancreatic cancer and the specific genomic and molecular alterations associated with disease subtypes. Here, we carry out an integrative bioinformatics analysis of The Cancer Genome Atlas dataset, including proteomics and whole-exome sequencing data collected from pancreatic cancer patients. We apply unsupervised clustering on the proteomics dataset to reveal the two distinct subtypes of pancreatic cancer. Using functional and pathway analysis based on the proteomics data, we demonstrate the different molecular processes and signalling aberrations of the pancreatic cancer subtypes. In addition, we explore the clinical characteristics of these subtypes to show differences in disease outcome. Using datasets of mutations and copy number alterations, we show that various signalling pathways previously associated with pancreatic cancer are altered among both subtypes of pancreatic tumours, including the Wnt pathway, Notch pathway and PI3K-mTOR pathways. Altogether, we reveal the proteogenomic landscape of pancreatic cancer subtypes and the altered molecular processes that can be leveraged to devise more effective treatments.

von Willebrand factor activity and activated partial thromboplastin time as proxy biomarkers for coagulopathies in women with menorrhagia in Zambia: a case-control study.

INTRODUCTION: von Willebrand Disease (vWD) is the most prevalent bleeding disorder. Women are more likely to manifest abnormal bleeding symptoms due to physiologic events and menorrhagia is the most common presenting symptom. METHODS: this case-control study included 168 women aged between 18 and 45. The cases had menorrhagia whilst the controls did not. Blood grouping, activated partial thromboplastin time and von Willebrand factor activity tests were performed on samples collected from consenting study participants. RESULTS: the mean age was 29.96 ± 7.37. Mean vWF activity of cases was 66.6% and of controls 97.8%. The mean activated Partial ThromboplastinTime (aPTT) of cases was 31.09s and of controls was 30.40s. There was no difference in the vWF activity between blood group O (86.3%) and non-blood group O (88.0%) participants. Eight women were diagnosed with von Willebrand disease, 6 cases and 2 controls. Higher odds of von Willebrand disease were seen in the cases (OR = 6.6). Epistaxis, von Willebrand and factor activity levels and family history of menorrhagia were associated with an increased risk for menorrhagia. CONCLUSION: von Willebrand factor activity levels were associated with menorrhagia while activated partial thromboplastin time was not. vWF activity levels did not depend on any specific blood group. The prevalence of von Willebrand disease was significantly higher in participants with menorrhagia and repeated epistaxis and family history of menorrhagia pointed to a higher risk of menorrhagia.

Cancer Stem Cell Marker CD44 Plays Multiple Key Roles in Human Cancers: Immune Suppression/Evasion, Drug Resistance, Epithelial-Mesenchymal Transition, and Metastasis.

One of the most frequently utilized cancer stem cell markers in human cancers, including colorectal cancer and breast cancer, is CD44. A glycoprotein, CD44, traverses the cell membrane and binds to many ligands, including hyaluronan, resulting in activation of signaling cascades. There are conflicting data, however, on expression of CD44 in relationship to subtypes of cancers. Moreover, the associations of CD44 expression with drug resistance, immune infiltration, epithelial-mesenchymal transition (EMT), metastasis, and clinical prognosis in several cancer types are not clear and call for further studies. We report here an original study on CD44 expression in several human cancers and its relationship with tumorigenesis. We harnessed data from the publicly available databases, including The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, Oncomine, Genomics of Drug Sensitivity in Cancer, and the Tumor Immune Estimation Resource. Our analysis reveals that CD44 expression varies across cancer types and is significantly associated with cancer patients' survival, in gastric and pancreatic cancers (p < 0.05). In addition, CD44 expression is closely linked with immune infiltration and immune suppressive features in pancreatic, colon adenocarcinoma, and stomach cancer. High CD44 expression was significantly correlated with the expression of drug resistance, EMT, and metastasis associated genes. Tumors expressing high CD44 have higher mutation burden and afflict older patients compared to tumors expressing low CD44. Cell lines expressing high CD44 are more resistant to anticancer drugs compared to those expressing low CD44. Protein-protein interaction investigations and functional enrichment analysis showed that CD44 interacts with gene products related to cell-substrate adhesion, migration, platelet activation, and cellular response to stress. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that these genes play key roles in biological adhesion, cell component organization, locomotion, G-α-signaling, and the response to stimulus. In summary, these findings lend evidence for the multiple key roles played by CD44 in tumorigenesis and suggest that CD44 is considered further in future studies of cancer pathogenesis and the search for novel molecular targets and personalized medicine biomarkers in clinical oncology.

High ELF4 expression in human cancers is associated with worse disease outcomes and increased resistance to anticancer drugs.

The malignant phenotype of tumour cells is fuelled by changes in the expression of various transcription factors, including some of the well-studied proteins such as p53 and Myc. Despite significant progress made, little is known about several other transcription factors, including ELF4, and how they help shape the oncogenic processes in cancer cells. To this end, we performed a bioinformatics analysis to facilitate a detailed understanding of how the expression variations of ELF4 in human cancers are related to disease outcomes and the cancer cell drug responses. Here, using ELF4 mRNA expression data of 9,350 samples from the Cancer Genome Atlas pan-cancer project, we identify two groups of patient's tumours: those that expressed high ELF4 transcripts and those that expressed low ELF4 transcripts across 32 different human cancers. We uncover that patients segregated into these two groups are associated with different clinical outcomes. Further, we find that tumours that express high ELF4 mRNA levels tend to be of a higher-grade, afflict a significantly older patient population and have a significantly higher mutation burden. By analysing dose-response profiles to 397 anti-cancer drugs of 612 well-characterised human cancer cell lines, we discover that cell lines that expressed high ELF4 mRNA transcript are significantly less responsive to 129 anti-cancer drugs, and only significantly more response to three drugs: dasatinib, WH-4-023, and Ponatinib, all of which remarkably target the proto-oncogene tyrosine-protein kinase SRC and tyrosine-protein kinase ABL1. Collectively our analyses have shown that, across the 32 different human cancers, the patients afflicted with tumours that overexpress ELF4 tended to have a more aggressive disease that is also is more likely more refractory to most anti-cancer drugs, a finding upon which we could devise novel categorisation of patient tumours, treatment, and prognostic strategies.

Assessing required SARS-CoV-2 blanket testing rates for possible control of the outbreak in the epicentre Lusaka province of Zambia with consideration for asymptomatic individuals: A simple mathematical modelling study.

INTRODUCTION: The novel Coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), in Africa is characterised by a more substantial proportion of asymptomatic (or mildly symptomatic) individuals thought to be playing a role in the spread of the infection. The exact proportion and degree of infectiousness of asymptomatic individuals remains unclear. Studies however indicate that their management is crucial for control of SARS-CoV-2 transmission. METHODOLOGY: We developed a simplified deterministic susceptible-exposed-infectious-removed (SEIR) mathematical model to assess the effect of active isolation of SARS-CoV-2 infected but asymptomatic individuals through blanket testing for control of the outbreak in Lusaka Province of Zambia. Here we modelled two scenarios; (1) assuming asymptomatic individuals comprised 70% of all COVID-19 cases and (2) asymptomatic individuals comprised only 50% of the cases. For contrast, the model was assessed first under the assumption that asymptomatic individuals are equally as infectious as symptomatic individuals and then secondly, and more likely, assuming asymptomatic individuals are only half as infectious as symptomatic individuals. RESULTS: For the model assuming 70% asymptomatic cases, a minimum sustained daily blanket testing rate of ≥ 7911 tests/100000 population was sufficient to control the outbreak if asymptomatic individuals are only half as infectious while if equal infectiousness was assumed then a testing rate of ≥ 10028 tests/ 100000 population would be required. For 50% asymptomatic, minimum blanket testing rates of ≥ 4540 tests/ 100000 population was sufficient to control the outbreak at both assumed levels of infectiousness for asymptomatic individuals relative to symptomatic individuals. DISCUSSION AND CONCLUSION: Our model predicts that active isolation of COVID-19 cases, including asymptomatic individuals, through blanket testing can be used as a possible measure for the control of the SARS-Cov-2 transmission in Lusaka, Zambia, but it would come at a high cost.

Integrated molecular characterisation of the MAPK pathways in human cancers reveals pharmacologically vulnerable mutations and gene dependencies.

The mitogen-activated protein kinase (MAPK) pathways are crucial regulators of the cellular processes that fuel the malignant transformation of normal cells. The molecular aberrations which lead to cancer involve mutations in, and transcription variations of, various MAPK pathway genes. Here, we examine the genome sequences of 40,848 patient-derived tumours representing 101 distinct human cancers to identify cancer-associated mutations in MAPK signalling pathway genes. We show that patients with tumours that have mutations within genes of the ERK-1/2 pathway, the p38 pathways, or multiple MAPK pathway modules, tend to have worse disease outcomes than patients with tumours that have no mutations within the MAPK pathways genes. Furthermore, by integrating information extracted from various large-scale molecular datasets, we expose the relationship between the fitness of cancer cells after CRISPR mediated gene knockout of MAPK pathway genes, and their dose-responses to MAPK pathway inhibitors. Besides providing new insights into MAPK pathways, we unearth vulnerabilities in specific pathway genes that are reflected in the re sponses of cancer cells to MAPK targeting drugs: a revelation with great potential for guiding the development of innovative therapies.

Leucocytosis and Asymptomatic Urinary Tract Infections in Sickle Cell Patients at a Tertiary Hospital in Zambia.

Sickle cell anaemia (SCA) is an inherited disease resulting from mutations in the ß-globin chain of adult haemoglobin that results in the formation of homozygous sickle haemoglobin. It is associated with several complications including an altered blood picture and damage in multiple organs, including the kidneys. Kidney disease is seen in most patients with SCA and may affect glomerular and/or tubular function, thereby putting these patients at risk of urinary tract infections. However, there is a paucity of data on the prevalence of urinary tract infections (UTIs) among SCA patients in Zambia. This study aimed to determine the prevalence of UTIs and haematological and kidney function profiles among SCA patients at the University Teaching Hospitals, Lusaka, Zambia. This was a cross-sectional study conducted between April and July 2019 involving 78 SCA patients who presented at the UTH. Blood and midstream urine samples were collected from each participant using the standard specimen collection procedures. Full blood counts and kidney function tests were determined using Sysmex XT-4000i haematology analyser and the Pentra C200 by Horiba, respectively. Bacterial profiles of the urine samples were determined using conventional microbiological methods. We found that all the measured patients' haemoglobin (Hb) levels fell below the WHO-recommended reference range with a minimum of 5 g/dl, a maximum of 10.5 g/dl, and a mean of 8 ± 1 g/dl. Fifty percent of the participants had moderate anaemia, while the other 50% had severe anaemia. The minimum WBC count of the participants was 0.02 × 109/L with a maximum of 23.36 × 109/L and a mean of 13.48 ± 3.87 × 109/L. Using the one-way analysis of variance test, we found no significant difference in mean WBC count and Hb concentration across various age-group categories that we defined. Bacteriuria was found in 25% of participants. The most common bacterial isolates were Staphylococcus aureus (32%) and coagulase-negative Staphylococci (32%). Klebsiella pneumoniae was 16%. We found no significant association between bacterial isolates and white blood cell count, age groups, sex, and anaemia severity p = 0.41. None of the participants were diagnosed with kidney disease. There was a high prevalence of asymptomatic UTIs among SCA patients at UTH, which, when coupled with the marked leukocytosis and anaemia, may negatively impact the clinical outcome of the patients. Therefore, we recommend close monitoring of sickle cell patients in Zambia for such conditions to improve patients' outcomes.

Machine Learning and Network Analyses Reveal Disease Subtypes of Pancreatic Cancer and their Molecular Characteristics.

Given that the biological processes governing the oncogenesis of pancreatic cancers could present useful therapeutic targets, there is a pressing need to molecularly distinguish between different clinically relevant pancreatic cancer subtypes. To address this challenge, we used targeted proteomics and other molecular data compiled by The Cancer Genome Atlas to reveal that pancreatic tumours can be broadly segregated into two distinct subtypes. Besides being associated with substantially different clinical outcomes, tumours belonging to each of these subtypes also display notable differences in diverse signalling pathways and biological processes. At the proteome level, we show that tumours belonging to the less severe subtype are characterised by aberrant mTOR signalling, whereas those belonging to the more severe subtype are characterised by disruptions in SMAD and cell cycle-related processes. We use machine learning algorithms to define sets of proteins, mRNAs, miRNAs and DNA methylation patterns that could serve as biomarkers to accurately differentiate between the two pancreatic cancer subtypes. Lastly, we confirm the biological relevance of the identified biomarkers by showing that these can be used together with pattern-recognition algorithms to accurately infer the drug sensitivity of pancreatic cancer cell lines. Our study shows that integrative profiling of multiple data types enables a biological and clinical representation of pancreatic cancer that is comprehensive enough to provide a foundation for future therapeutic strategies.

Impact of Hormonal Contraceptives on Cervical T-helper 17 Phenotype and Function in Adolescents: Results from a Randomized, Crossover Study Comparing Long-acting Injectable Norethisterone Oenanthate (NET-EN), Combined Oral Contraceptive Pills, and Combined Contraceptive Vaginal Rings.

BACKGROUND: Adolescents in sub-Saharan Africa are at risk for human immunodeficiency virus (HIV) infection and unintended pregnancies. Observational studies suggest that injectable hormonal contraceptives (HCs) increase the HIV risk, although their effects on genital inflammation, particularly HIV-susceptible T-helper 17 (Th17) cells, are unknown. In a randomized crossover study, the effect of injectable norethisterone oenanthate (NET-EN), combined contraceptive vaginal rings (CCVR; NuvaRing), and combined oral contraceptive pills (COCPs) on cervical Th17 cells and cytokines were compared. METHODS: Adolescents (n = 130; 15-19 years) were randomly assigned 1:1:1 to NET-EN, CCVR, or COCPs for 16 weeks, then subsequently crossed over to another HC for 16 weeks. Estrogen, follicular stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured. Chemokine receptor 5 (CCR5), human leukocyte antigen (HLA) DR isotope, and cluster of differentiation 38 (CD38) expression by cervical cytobrush-derived CD4+ T cells was assessed by fluorescence-activated cell sorting. Th17 cells were defined as CCR6+ and CCR10-. Cervicovaginal Th17-related cytokines were measured by Luminex. RESULTS: CCVR use for the first 16 weeks was associated with reduced Th17 frequencies and lower FSH and LH concentrations, as compared to NET-EN and COCPs, with FSH concentrations and Th17 frequencies correlating significantly. However, Th17-related cytokine concentrations (interleukin [IL]-21, IL-1ß, tumor necrosis factor-α, interferon-γ) and CCR5, HLA-DR, CD38, and Th17 frequencies were significantly higher in CCVR than NET-EN and COCP. At crossover, CCVR users changing to COCPs or NET-EN did not resolve activation or cytokines, although switching from COCP to CCVRs increased cytokine concentrations. CONCLUSIONS: CCVR use altered endogenous hormone levels and associated cervical Th17 cell frequencies to a greater extent than use of NET-EN or COCPs, although Th17 cells were more activated and Th17-related cytokine concentrations were elevated. While CCVRs may impact the HIV risk by regulating Th17 numbers, increased activation and inflammation may balance any risk gains.

Metabolic gene alterations impact the clinical aggressiveness and drug responses of 32 human cancers.

Malignant cells reconfigure their metabolism to support oncogenic processes such as accelerated growth and proliferation. The mechanisms by which this occurs likely involve alterations to genes that encode metabolic enzymes. Here, using genomics data for 10,528 tumours of 32 different cancer types, we characterise the alterations of genes involved in various metabolic pathways. We find that mutations and copy number variations of metabolic genes are pervasive across all human cancers. Based on the frequencies of metabolic gene alterations, we further find that there are two distinct cancer supertypes that tend to be associated with different clinical outcomes. By utilising the known dose-response profiles of 825 cancer cell lines, we infer that cancers belonging to these supertypes are likely to respond differently to various anticancer drugs. Collectively our analyses define the foundational metabolic features of different cancer supertypes and subtypes upon which discriminatory strategies for treating particular tumours could be constructed.

Integrative landscape of dysregulated signaling pathways of clinically distinct pancreatic cancer subtypes.

Despite modern therapeutic advances, the survival prospects of pancreatic cancer patients have remained poor. Besides being highly metastatic, pancreatic cancer is challenging to treat because it is caused by a heterogeneous array of somatic mutations that impact a variety of signaling pathways and cellular regulatory systems. Here we use publicly available transcriptomic, copy number alteration and mutation profiling datasets from pancreatic cancer patients together with data on disease outcomes to show that the three major pancreatic cancer subtypes each display distinctive aberrations in cell signaling and metabolic pathways. Importantly, patients afflicted with these different pancreatic cancer subtypes also exhibit distinctive survival profiles. Within these patients, we find that dysregulation of the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways, and p53 mediated disruptions of cell cycle processes are apparently drivers of disease. Further, we identify for the first time the molecular perturbations of signalling networks that are likely the primary causes of oncogenesis in each of the three pancreatic cancer subtypes.