A benchmark of computational methods for correcting biases of established and unknown origin in CRISPR-Cas9 screening data.

Background: CRISPR-Cas9 dropout screens are formidable tools for investigating biology with unprecedented precision and scale. However, biases in data lead to potential confounding effects on interpretation and compromise overall quality. The activity of Cas9 is influenced by structural features of the target site, including copy number amplifications (CN bias).

Germline variation contributes to false negatives in CRISPR-based experiments with varying burden across ancestries.

Reducing disparities is vital for equitable access to precision treatments in cancer. Socioenvironmental factors are a major driver of disparities, but differences in genetic variation likely also contribute. The impact of genetic ancestry on prioritization of cancer targets in drug discovery pipelines has not been systematically explored due to the absence of pre-clinical data at the appropriate scale.

Chronos: a cell population dynamics model of CRISPR experiments that improves inference of gene fitness effects.

CRISPR loss of function screens are powerful tools to interrogate biology but exhibit a number of biases and artifacts that can confound the results. Here, we introduce Chronos, an algorithm for inferring gene knockout fitness effects based on an explicit model of cell proliferation dynamics after CRISPR gene knockout. We test Chronos on two pan-cancer CRISPR datasets and one longitudinal CRISPR screen.

Integrated cross-study datasets of genetic dependencies in cancer.

CRISPR-Cas9 viability screens are increasingly performed at a genome-wide scale across large panels of cell lines to identify new therapeutic targets for precision cancer therapy. Integrating the datasets resulting from these studies is necessary to adequately represent the heterogeneity of human cancers and to assemble a comprehensive map of cancer genetic vulnerabilities. Here, we integrated the two largest public independent CRISPR-Cas9 screens performed to date (at the Broad and Sanger institutes) by assessing, comparing, and selecting methods for correcting biases due to heterogeneous single-guide RNA efficiency, gene-independent responses to CRISPR-Cas9 targeting originated from copy number alterations, and experimental batch effects.

Alteration of the circadian rhythm of intact parathyroid hormone and serum phosphate in women with established postmenopausal osteoporosis.

Several studies have established that the circulating concentration of intact parathyroid hormone, PTH (1-84), over 24 h follows a circadian rhythm. The importance of this circadian rhythm is not known although some authors have detected alterations in the rhythm in metabolic bone disease and following dietary manipulation. We have studied the circadian rhythm of PTH (1-84) in 8 premenopausal women, 8 postmenopausal women with established osteoporosis and 8 postmenopausal women with no evidence of osteoporosis.

Management of male osteoporosis: report of the UK Consensus Group.

Although osteoporosis is generally regarded as a disease of women, up to 30% of hip fractures and 20% of vertebral fractures occur in men. Risk factors for osteoporotic fractures in men include low body mass index, smoking, high alcohol consumption, corticosteroid therapy, physical inactivity, diseases that predispose to low bone mass, and conditions increasing the risk of falls. The key drugs and diseases that definitely produce a decrease in bone mineral density (BMD) and/or an increase in fracture rate in men are long-term corticosteroid use, hypogonadism, alcoholism and transplantation.

A comparison of the effects of alfacalcidol treatment and vitamin D2 supplementation on calcium absorption in elderly women with vertebral fractures.

Although vitamin D supplementation in the frail elderly improves calcium absorption, suppresses parathyroid hormone, decreases bone loss and reduces the risk of fractures, such treatment may be ineffective in patients with vertebral osteoporosis, because of impaired vitamin D metabolism or resistance to the action of vitamin D metabolites on the bowel. We have therefore performed a randomized, single masked study comparing the effects of alfacalcidol treatment (0.25 micrograms twice daily) and vitamin D2 supplementation (500-1000 units daily) on calcium absorption and bone turnover in 46 elderly women (median age 69 years, range 64-79 years) with radiological evidence of vertebral fractures.

Changes in calciotrophic hormones and biochemical markers of bone turnover in normal human pregnancy.

Plasma concentrations of parathyroid hormone-related protein (PTHrP), parathyroid hormone, alkaline phosphatase, osteocalcin and albumin-adjusted calcium were measured along with nephrogenous cyclic adenosine monophosphate (NcAMP) in 10 normal women longitudinally through pregnancy. In addition, an assessment of bone resorption was made in these same subjects by the measurement in true fasting urine specimens of the calcium/creatinine ratio (Ca/Cr), hydroxyproline/creatinine ratio (HP/Cr), pyridinoline/creatinine ratio (Pyr/Cr) and deoxypyridinoline/creatine ratio (Dpyr/Cr). The PTHrP level rose through pregnancy from (mean +/- SEM) 0.

Recurrent chylothorax in a woman with primary amenorrhoea.

A 47 year old woman receiving oestrogen replacement therapy for primary amenorrhoea presented with recurrent chylothorax. The clinical and radiological features of her illness were characteristic of pulmonary lymphangio-leiomyomatosis, a rare hormone-dependent disease. The condition was treated with pleurodesis and withdrawal of oestrogen therapy.

Cytokine and growth factor expression in Paget's disease: analysis by reverse-transcription/polymerase chain reaction.

We investigated expression of several cytokines and growth factors in explants of Pagetic and non-Pagetic bone samples using the technique of reverse-transcription/polymerase chain reaction (RT/PCR). Transcripts for IL-1 alpha and IL-1 beta, TNF-alpha, TNF-beta, IL-6, basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-beta) and insulin-like growth factor-I (IGF-I) were found to a variable degree in both Pagetic and non-Pagetic bone samples, but there was no significant difference in the patterns of expression for these factors in Pagetic bone (n = 18) as compared with non-Pagetic bone (n = 51). There was furthermore, no significant difference in the patterns of expression for the various factors studied when patients were subdivided into mild and severe categories of disease activity using markers of bone formation (serum alkaline phosphatase) or bone resorption (osteoclast counts on adjacent biopsy specimens).

Association of severe haemophilia A with osteoporosis: a densitometric and biochemical study.

Following a femoral neck fracture and vertebral compression fractures in two patients with severe haemophilia A, bone density and turnover were measured in 19 males with severe haemophilia A (all HIV negative, 18/19 hepatitis C antibody positive) and in 19 age/sex matched controls. Bone density at the lumbar spine (L2-4), measured by dual energy X-ray absorptiometry, was significantly lower in the haemophiliac patients (HPs) at (mean +/- SEM) 1.109 +/- 0.

Acute effects of intravenous 1 alpha-hydroxycholecalciferol on parathyroid hormone, osteocalcin and calcitriol in man.

The acute effects of a single intravenous injection of 2 micrograms of 1 alpha-hydroxycholecalciferol (alfacalcidol) were studied for a 24-h period in six normal males (mean age 33 years), six women with primary hyperparathyroidism (mean age 72 years) and six women with established osteoporosis (mean age 63 years). In all three groups, serum calcitriol levels rose to a peak 2-3 h after administration of alfacalcidol. Basal levels were highest in the primary hyperparathyroidism group at (mean +/- SEM) 81 +/- 2 vs 62 +/- 12 (normal males) (p < 0.

Mineralisation defects with pamidronate therapy for Paget's disease.

Bone biopsy samples were taken from 20 patients with Paget's disease before and after intravenous pamidronate therapy. In 10 patients given 180 or 360 mg during 6 or 9 weeks, bone turnover decreased as measured biochemically and histologically, but osteomalacia developed in 1 patient and mineralisation defects in 3. 10 other patients received 45 mg every 3 months for 1 year.

Secondary osteoporosis.

Osteoporosis with attendant increased fracture risk is a common complication of many other diseases. Indeed, almost all chronic diseases make some impact on life-style, usually by restricting physical activity and hence reducing the anabolic effect of exercise and gravitational strains on the skeleton. Restricted appetite and modified gastrointestinal tract function is another commonplace finding that has an impact on bone nutrition and synthesis, as on other systems.

Central nervous system histiocytosis X--imaging and responses to chemotherapy.

Histiocytosis X is the term first coined by Lichtenstein in 1953 to describe a heterogeneous group of disorders which is considered now to include Hand-Schuller-Christian disease, Letterer-Siwe disease and Eosinophilic Granuloma of bone. Gagel, in 1941, first described involvement of the central nervous system (CNS) in Histiocytosis X--in this case the hypothalamus and posterior pituitary were the areas principally affected. CNS involvement outwith these areas is rare, generally difficult to diagnose, and little information on treatment is available.

A comparison of 10 MHz ultrasound and 201-thallium/99m-technetium subtraction scanning in primary hyperparathyroidism.

Both high resolution (10 MHz) ultrasound and 201-thallium/99m-technetium subtraction scanning (Tl/Tc) were carried out preoperatively in 25 patients with primary hyperparathyroidism. Operative findings were the standard against which these two imaging methodologies were compared. Tl/Tc scanning showed a sensitivity of 42% and a specificity of 97%.

Coincidental occurrence of primary hyperparathyroidism and cancer-associated hypercalcaemia in a middle-aged man.

Primary hyperparathyroidism (PHPT) is found not uncommonly in patients with cancer. In this report, however, we describe a patient where both humoral hypercalcaemia of malignancy and PHPT were present coincidentally. A 47-year-old man was found to have PHPT due to parathyroid hyperplasia.

Clinical and laboratory studies of a new immunoradiometric assay of parathyroid hormone-related protein.

Parathyroid hormone-related protein (PTHrP) was measured in plasma by a new immunoradiometric assay (IRMA) from Nichols Institute. The assay is specific for PTHrP and shows excellent parallelism when measuring keratinocyte fluid, samples with high PTHrP content, and PTHrP-supplemented plasma. A precision profile established the assay detection limit at 0.

An evaluation of bone density and turnover in premenopausal women with type 1 diabetes mellitus.

Measurement of bone density and turnover was assessed in 20 premenopausal females with Type 1 diabetes mellitus and 27 age-sex-matched controls. Measurement was made of spinal (L2-4) and neck of femur bone density by dual-energy X-ray absorptiometry. L2-4 density was significantly higher in the diabetic patients compared with controls (1.