Proliferation dynamics of acute myeloid leukaemia and haematopoietic progenitors competing for bone marrow space.

Leukaemia progressively invades bone marrow (BM), outcompeting healthy haematopoiesis by mechanisms that are not fully understood. Combining cell number measurements with a short-timescale dual pulse labelling method, we simultaneously determine the proliferation dynamics of primitive haematopoietic compartments and acute myeloid leukaemia (AML). We observe an unchanging proportion of AML cells entering S phase per hour throughout disease progression, with substantial BM egress at high levels of infiltration. For healthy haematopoiesis, we find haematopoietic stem cells (HSCs) make a significant contribution to cell production, but we phenotypically identify a quiescent subpopulation with enhanced engraftment ability. During AML progression, we observe that multipotent progenitors maintain a constant proportion entering S phase per hour, despite a dramatic decrease in the overall population size. Primitive populations are lost from BM with kinetics that are consistent with ousting irrespective of cell cycle state, with the exception of the quiescent HSC subpopulation, which is more resistant to elimination.

The mTOR inhibitor rapamycin opposes carcinogenic changes to epidermal Akt1/PKBα isoform signaling.

Epidermal squamous cell carcinoma (SCC) is the most aggressive non-melanoma skin cancer and is dramatically increased in patients undergoing immunosuppression following solid organ transplantation, contributing substantially to morbidity and mortality. Recent clinical studies show that use of the mammalian target of rapamycin (mTOR) inhibitor rapamycin as a post-transplantation immunosuppressive significantly reduces SCC occurrence compared with other immunosuppressives, though the mechanism is not fully understood. We show that rapamycin selectively upregulates epidermal Akt1, while failing to upregulate epidermal Akt2. Rapamycin increases epidermal Akt1 phosphorylation via inhibition of the mTOR complex 1-dependent regulation of insulin receptor substrate-1. Epidermal Akt1 is commonly downregulated in SCC while Akt2 is upregulated. We now demonstrate similar Akt1 downregulation and Akt2 upregulation by ultraviolet (UV) radiation, the most important skin carcinogen. Hence, rapamycin's upregulation of Akt1 signaling could potentially oppose the effects of UV radiation and/or tumor-associated changes on Akt1 signaling. We show in skin culture that rapamycin does enhance restoration of Akt1 phosphorylation in skin recovering from UV radiation, suggesting a mechanism for rapamycin's antitumor activity in epidermis in spite of its efficient immunosuppressive properties.

Pulmonary metastatic malignant tumours in Ibadan, Nigeria: 10 years autopsy review.

This study reports the findings of a ten year review of autopsy records at the University College Hospital, Ibadan, Nigeria of patients who died of malignant tumour metastases to the lungs and pleurae. During the study period 1977 to 1986, a total of 3,549 autopsies were performed out of which 339 cases 10.5 pc died of malignant tumours. One hundred and thirteen of these tumours (33.3 pc) metastasised to the lungs and pleurae among other sites. Further analysis of these 113 patients showed that 49 were male and 64 females giving a male:female ratio of 1:1,3. In addition, the ages of the patients ranged between 9 months and 90 years with a mean of 38.3 years. The uterus was the commonest organ from which pulmonary metastases occurred (28.3 pc), with choriocarcinoma being the predominant historical type of uterine tumour. The liver was the next most common organ 26.5 pc with male to female ration of 3:3,1. Twenty other organs were also identified, the breast, kidney and oesophagus 7 pc each; pancreas ovary and thyroid 3 pc each being the most important. Other organs are adrenals, foot, neck, cervix and rectum--2 pc each.