Lethal phenotypes in Mendelian disorders.

PURPOSE: Existing resources that characterise the essentiality status of genes are based on either proliferation assessment in human cell lines, viability evaluation in mouse knockouts, or constraint metrics derived from human population sequencing studies. Several repositories document phenotypic annotations for rare disorders, however there is a lack of comprehensive reporting on lethal phenotypes. METHODS: We queried Online Mendelian Inheritance in Man for terms related to lethality and classified all Mendelian genes according to the earliest age of death recorded for the associated disorders, from prenatal death to no reports of premature death. We characterised the genes across these lethality categories, examined the evidence on viability from mouse models and explored how this information could be used for novel gene discovery. RESULTS: We developed the Lethal Phenotypes Portal to showcase this curated catalogue of human essential genes. Differences in the mode of inheritance, physiological systems affected and disease class were found for genes in different lethality categories as well as discrepancies between the lethal phenotypes observed in mouse and human. CONCLUSION: We anticipate that this resource will aid clinicians in the diagnosis of early lethal conditions and assist researchers in investigating the properties that make these genes essential for human development.

Lethal phenotypes in Mendelian disorders.

Essential genes are those whose function is required for cell proliferation and/or organism survival. A gene's intolerance to loss-of-function can be allocated within a spectrum, as opposed to being considered a binary feature, since this function might be essential at different stages of development, genetic backgrounds or other contexts. Existing resources that collect and characterise the essentiality status of genes are based on either proliferation assessment in human cell lines, embryonic and postnatal viability evaluation in different model organisms, and gene metrics such as intolerance to variation scores derived from human population sequencing studies. There are also several repositories available that document phenotypic annotations for rare disorders in humans such as the Online Mendelian Inheritance in Man (OMIM) and the Human Phenotype Ontology (HPO) knowledgebases. This raises the prospect of being able to use clinical data, including lethality as the most severe phenotypic manifestation, to further our characterisation of gene essentiality. Here we queried OMIM for terms related to lethality and classified all Mendelian genes into categories, according to the earliest age of death recorded for the associated disorders, from prenatal death to no reports of premature death. To showcase this curated catalogue of human essential genes, we developed the Lethal Phenotypes Portal (https://lethalphenotypes.research.its.qmul.ac.uk), where we also explore the relationships between these lethality categories, constraint metrics and viability in cell lines and mouse. Further analysis of the genes in these categories reveals differences in the mode of inheritance of the associated disorders, physiological systems affected and disease class. We highlight how the phenotypic similarity between genes in the same lethality category combined with gene family/group information can be used for novel disease gene discovery. Finally, we explore the overlaps and discrepancies between the lethal phenotypes observed in mouse and human and discuss potential explanations that include differences in transcriptional regulation, functional compensation and molecular disease mechanisms. We anticipate that this resource will aid clinicians in the diagnosis of early lethal conditions and assist researchers in investigating the properties that make these genes essential for human development.

Cabozantinib and dasatinib synergize to induce tumor regression in non-clear cell renal cell carcinoma.

The lack of effective treatment options for advanced non-clear cell renal cell carcinoma (NCCRCC) is a critical unmet clinical need. Applying a high-throughput drug screen to multiple human kidney cancer cells, we identify the combination of the VEGFR-MET inhibitor cabozantinib and the SRC inhibitor dasatinib acts synergistically in cells to markedly reduce cell viability. Importantly, the combination is well tolerated and causes tumor regression in vivo. Transcriptional and phosphoproteomic profiling reveals that the combination converges to downregulate the MAPK-ERK signaling pathway, a result not predicted by single-agent analysis alone. Correspondingly, the addition of a MEK inhibitor synergizes with either dasatinib or cabozantinib to increase its efficacy. This study, by using approved, clinically relevant drugs, provides the rationale for the design of effective combination treatments in NCCRCC that can be rapidly translated to the clinic.

Pelvic Floor Physical Therapy and Women's Health Promotion.

Pelvic floor dysfunction is defined as abnormal function of the pelvic floor and includes conditions that can have significant adverse impacts on a woman's quality of life, including urinary incontinence (stress, urge, and mixed), fecal incontinence, pelvic organ prolapse, sexual dysfunction, diastasis recti abdominis, pelvic girdle pain, and chronic pain syndromes. Women's health care providers can screen for, identify, and treat pelvic floor dysfunction. This article examines the case of a woman with multiple pelvic-floor-related problems and presents the evidence for the use of pelvic floor physical therapy (PFPT) for pregnancy-related pelvic floor dysfunction. PFPT is an evidence-based, low-risk, and minimally invasive intervention, and women's health care providers can counsel women about the role that PFPT may play in the prevention, treatment, and/or management of pelvic floor dysfunction.

New developments in long-acting reversible contraception: the promise of intrauterine devices and implants to improve family planning services.

After decades of having the developed world's highest rates of unintended pregnancy, the United States finally shows signs of improvement. This progress is likely due in large part to increased use of highly effective long-acting reversible methods of contraception. These methods can be placed and do not require any maintenance to provide years of contraception as effective as sterilization. Upon removal, fertility returns to baseline rates. This article addresses advances in both software-improved use and elimination of barriers to provide these methods; and hardware-novel delivery systems and devices.