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Mathieu Lupien and colleagues report an enrichment of somatic mutations at the ESR1 cis -regulatory region in 7% of ESR1-positive breast cancers. They find that the activity of the recurrently mutated ESR1 enhancer is also influenced by breast cancer risk–associated SNPs. Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program 1 . Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers 2 , 3 , 4 , 5 , suggesting that other mechanisms underlie the persistent expression of ESR1 . We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer risk–associated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer.

It is well known that protein tyrosine phosphatases (PTPs) that become oxidized due to exposure to reactive oxygen species (ROS) undergo a conformational change and are inactivated. However, whether PTPs can actively regulate ROS levels in order to prevent PTP inhibition has yet to be investigated. Here, we demonstrate that PTP non-receptor type 12 (PTPN12) protects cells against aberrant ROS accumulation and death induced by oxidative stress. Murine embryonic fibroblasts (MEFs) deficient in PTPN12 underwent increased ROS-induced apoptosis under conditions of antioxidant depletion. Cells lacking PTPN12 also showed defective activation of FOXO1/3a, transcription factors required for the upregulation of several antioxidant genes. PTPN12-mediated regulation of ROS appeared to be mediated by phosphoinositide-dependent kinase-1 (PDK1), which was hyperstimulated in the absence of PTPN12. As tight regulation of ROS to sustain survival is a key feature of cancer cells, we examined PTPN12 levels in tumors from a cohort of breast cancer patients. Patients whose tumors showed high levels of PTPN12 transcripts had a significantly poorer prognosis. Analysis of tissues from patients with various breast cancer subtypes revealed that more triple-negative breast cancers, the most aggressive breast cancer subtype, showed high PTPN12 expression than any other subtype. Furthermore, both human breast cancer cells and mouse mammary epithelial tumor cells engineered to lack PTPN12 exhibited reduced tumorigenic and metastatic potential in vivo that correlated with their elevated ROS levels. The involvement of PTPN12 in the antioxidant response of breast cancer cells suggests that PTPN12 may represent a novel therapeutic target for this disease.

BackgroundChlamydia Psittaci infection is rare in pregnancy but can be associated with severe feto-maternal morbidity and mortality. Failure to identify at risk patients may delay diagnosis and appropriate treatment.CaseA 30 year old nulliparous woman presented at 31 weeks gestation with pyrexia, vomiting and malaise. She had no significant past medical or drug history. On examination she was pyrexial, tachycardic and hypoxic. Cardiotocography showed no evidence of foetal compromise. Blood tests revealed an inflammatory picture associated with new anaemia, thrombocytopenia, impaired renal function and deranged liver function enzymes. Chest radiography showed perihilar consolidation. Oxygen therapy, intravenous fluid resuscitation and broad spectrum antibiotics were commenced. Complement fixation testing showed a raised chlamydia psittaci titre. Indirect history revealed exposure to infected parrots at the patient's place of work as the most likely source of infection. Antibiotics were changed from a broad spectrum regime to macrolide antibiotics; the patient then improved and was discharged 5 days later. Her pregnancy was subsequently uncomplicated and she had a spontaneous onset delivery at 38 weeks gestation.DiscussionChlamydia Psittaci, whilst rare, should be considered in patients presenting with severe sepsis in pregnancy. When identified early and treated with macrolide antibiotics, feto-maternal morbidity may be prevented. Thorough history taking would allow Obstetricians to identify high risk women and deliver advice to avoid exposure, subsequent infection and adverse outcomes.

Background Chlamydia Psittaci infection is rare in pregnancy but can be associated with severe feto-maternal morbidity and mortality. Failure to identify at risk patients may delay diagnosis and appropriate treatment. Case A 30 year old nulliparous woman presented at 31 weeks gestation with pyrexia, vomiting and malaise. She had no significant past medical or drug history. On examination she was pyrexial, tachycardic and hypoxic. Cardiotocography showed no evidence of foetal compromise. Blood tests revealed an inflammatory picture associated with new anaemia, thrombocytopenia, impaired renal function and deranged liver function enzymes. Chest radiography showed perihilar consolidation. Oxygen therapy, intravenous fluid resuscitation and broad spectrum antibiotics were commenced. Complement fixation testing showed a raised chlamydia psittaci titre. Indirect history revealed exposure to infected parrots at the patient’s place of work as the most likely source of infection. Antibiotics were changed from a broad spectrum regime to macrolide antibiotics; the patient then improved and was discharged 5 days later. Her pregnancy was subsequently uncomplicated and she had a spontaneous onset delivery at 38 weeks gestation. Discussion Chlamydia Psittaci, whilst rare, should be considered in patients presenting with severe sepsis in pregnancy. When identified early and treated with macrolide antibiotics, feto-maternal morbidity may be prevented. Thorough history taking would allow Obstetricians to identify high risk women and deliver advice to avoid exposure, subsequent infection and adverse outcomes.

The frequency distributions for age at menarche and for age at menopause are given for 324 women whose menstrual histories have been recorded from their university student days (1934-38 ) until natural menopause terminated their potential for reproduction. Age at menarche is not correlated with age at menopause. The difference between these two ages is accepted as measuring the maximum possible length of potential reproductive life. A mean age at menarche of 13.6 years, and at menopause of 49.5 years, gives an average length of menstrual life of 35.9 years for the cases studied. Variation in age at menopause is shown to be 2.2 times that of age at menarche. Since these 2 ages are independent, length of menstrual life is even more variable than age at menopause, with which it is strongly correlated (r =+0.91). Age at menarche influences length of menstrual life only slightly (r =-0.38). Age at menarche is well known to show secular change. Data accumulating within this research program suggests that average age at menarche in the USA may have begun an upswing in recent decades. Maximum reproduction potential, attainable only in theory by assuming all menstrual cycles produce ova of undiminished capacity to become fertilised, can be defined by combining the cumulative frequency curve for age at menarche with the inverse of that for age at menopause. The influence of \"anovulatory menstrual cycles\" in reducing that potential is illustrated using Vollman's conclusions from his extensive basal body temperature histories. All pregnancies as well as breast feeding operate to reduce fecundability. The various contraceptive measures used by mankind also lower reproductive performance until the fecundability curve becomes the curve of realized fertility. The collective impact of pregnancy and contraceptive practises in lowering the reproduction expectancy curve is used as a measure of control of conception.