Competitive clonal hematopoiesis in mouse chimeras explained by a stochastic model of stem cell organization

Many current experimental results show the necessity of new conceptual approaches to understand hematopoietic stem cell organization. Recently, we proposed a novel theoretical concept and a corresponding quantitative model based on microenvironment-dependent stem cell plasticity. The objective of our present work is to subject this model to an experimental test for the situation of chimeric hematopoiesis. Investigating clonal competition processes in DBA/2-C57BL/6 mouse chimeras, we observed biphasic chimerism development with initially increasing but long-term declining DBA/2 contribution. These experimental results were used to select the parameters of the mathematical model. To validate the model beyond this specific situation, we fixed the obtained parameter configuration to simulate further experimental settings comprising variations of transplanted DBA/2-C57BL/6 proportions, secondary transplantations, and perturbation of stabilized chimeras by cytokine and cytotoxic treatment. We show that the proposed model is able to consistently describe the situation of chimeric hematopoiesis. Our results strongly support the view that the relative growth advantage of strain-specific stem cells is not a fixed cellular property but is sensitively dependent on the actual state of the entire system. We conclude that hematopoietic stem cell organization should be understood as a flexible, self-organized rather than a fixed, preprogrammed process.     

Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL

Cyclophosphamide, doxorubicin, vincristine, and prednisone, given every 3 weeks (CHOP-21), is standard chemotherapy for aggressive lymphomas. To determine whether biweekly CHOP (CHOP-14) with or without etoposide is more effective than CHOP-21, 689 patients ages 61 to 75 years were randomized to 6 cycles of CHOP-21, CHOP-14, CHOEP-21 (CHOP plus etoposide 100 mg/m2 days 1-3), or CHOEP-14. Patients in the 2-weekly regimens received granulocyte colony-stimulating factor (G-CSF) starting from day 4. Patients received radiotherapy (36 Gy) to sites of initial bulky disease and extranodal disease. Complete remission rates were 60.1% (CHOP-21), 70.0% (CHOEP-21), 76.1% (CHOP-14), and 71.6% (CHOEP-14). Five-year event-free and overall survival rates were 32.5% and 40.6%, respectively, for CHOP-21 and 43.8% and 53.3%, respectively, for CHOP-14. In a multivariate analysis, the relative risk reduction was 0.66 (P =.003) for event-free and 0.58 (P <.001) for overall survival after CHOP-14 compared with CHOP-21. Toxicity of CHOP-14 and CHOP-21 was similar, but CHOEP-21 and in particular CHOEP-14 were more toxic. Due to its favorable efficacy and toxicity profile, CHOP-14 should be considered the new standard chemotherapy regimen for patients ages 60 or older with aggressive lymphoma.     

Sleep behavior of underrepresented youth

Aim

In a disadvantageous socioeconomic context, minority children’s sleep ecology and hygiene may promote poor sleep.

Subjects and methods

A de-identified questionnaire was randomly distributed in local community centers. Subjects were a posteriori stratified into lower class (59.5 %), middle class (22.2 %) and upper class (18.4 %), and into the age categories used in the National Sleep Foundation Polls.

Results

The sample (n?=?221) comprised 85.4 % African Americans, 9.1 % Hispanics and 5.6 % Mixed Ethnicities, which were equally distributed across classes. The respondent was primarily the mother (64.4 %), and the questionnaire information reflected the sleep of 7.0?±?4.5 year olds, 49.5 % of which were girls. Co-sleeping was done by 43.5 %, and 76.8 % had a television in the room. Almost 45 % of the children went to bed on their own. Given the age range, the already insufficient amount of nighttime sleep was further reduced by poor sleep hygiene or ecology by about an hour. Sleep problems reported indicated difficulties with initiating and maintaining sleep.

Conclusion

Underrepresented youth have problematic sleep, which is characterized by difficulties initiating and maintaining sleep, or sleep-impeding circumstances. Sleep interventions in the underprivileged aiming at improving sleep hygiene and ecology should be developed.     

Extramedullary multiple myeloma involving the liver and periportal lymph node,diagnosed by EUS‐FNA in a patient with cirrhosis

Extramedullary multiple myeloma (EMM) involving the liver as a focal space‐occupying lesion is very rare, especially in the patients with cirrhosis. Here, we report a case of EMM in the liver and periportal lymph node, diagnosed by endoscopic ultrasound guided‐fine‐needle aspiration (EUS‐FNA). A 57‐year‐old male patient, with history of cirrhosis, presented with abdominal pain and pancytopenia. The abdominal magnetic resonance imaging (MRI) demonstrated a 6.5 cm left hepatic mass with a 1.1 cm malignant‐appearing periportal lymph node and diffuse osseous lesions. The cytology specimens from the hepatic mass and the periportal lymph node were obtained through EUS‐FNA without rapid on‐site evaluation (ROSE). The thin‐layer preparations (ThinPrep) showed abundant plasmacytoid cells, which were confirmed to be Kappa‐restricted neoplastic plasma cells by the cell block preparations. Later, his serum level of Kappa light chain was found significantly elevated by flow cytometry, which was identified as monoclonal IgA Kappa light chain by serum protein electrophoresis (SPEP) with immunofixation. The patient was diagnosed as IgA multiple myeloma with extramedullary involvement of the liver and periportal lymph node. This is the first case showing the ThinPrep cytomorphologic features of EMM in the liver and periportal lymph node. This case highlights the importance of distinguishing plasma cells from being hepatocytes and lymphocytes on the ThinPrep and also emphasizes the utility of the cell block in the diagnosis of plasma cell neoplasm.     

5-fluorouracil metabolite patterns in viable and necrotic tumor areas of murine colon carcinoma determined by 19F NMR spectroscopy

High-resolution ¹⁹F NMR spectroscopy at 9.4 T was used to study the difference in the metabolite pattern of 5-fluorouracil (5-FU) between viable and necrotic tissues of C38 murine colon tumors grown in C57BI/6 mice. Studies were performed on perchloric acid extracts of these tumor fractions after 5-FU treatment. The ¹⁹F nuclear magnetic resonance spectra exhibited resonances representing 5-FU, the catabolites α-fluoro-β-ureidopropionic acid and α-fluoro-β-alanine, as well as several fluoronucleotide anabolites. The absolute concentrations of anabolites and catabolites and the anabolite-to-catabolite ratio were significantly lower in the necrotic fraction than in the viable tumor fraction 50 min after administration of 5-FU, whereas the absolute concentration of 5-FU was the same. Therefore, in 5-FU metabolism studies with NMR spectroscopy, it is important to consider the necrotic contribution to the tumor volume.     

Psoriasis risk genes of the late cornified envelope-3 group are distinctly expressed compared with genes of other LCE groups

Deletion of the late cornified envelope (LCE) genes LCE3B and LCE3C has recently been identified as a risk factor for psoriasis. Expression of 16 LCE genes of LCE groups 1, 2, 3, 5, and 6 was examined in vivo and in vitro. Quantitative PCR demonstrated that moderate to high LCE expression was largely confined to skin and a few oropharyngeal tissues. Genes of the LCE3 group demonstrated increased expression in lesional psoriatic epidermis and were induced after superficial injury of normal skin, whereas expression of members of other LCE groups was down-regulated under these conditions. Immunohistochemistry and immunoelectron microscopy demonstrated that LCE2 protein expression was restricted to the uppermost granular layer and the stratum corneum. Stimulation of in vitro reconstructed skin by several psoriasis-associated cytokines resulted in induction of LCE3 members. The data suggest that LCE proteins of groups 1, 2, 5, and 6 are involved in normal skin barrier function, whereas LCE3 genes encode proteins involved in barrier repair after injury or inflammation. These findings may provide clues to the mechanistic role of LCE3B/C deletion in psoriasis.     

Comparison between plasma and whole blood specimens for detection of Aspergillus DNA by PCR

Ninety-six plasma and whole blood specimens from nine selected patients were analyzed for the presence of Aspergillus DNA. Nineteen specimens from three patients with proven aspergillosis were PCR positive in both materials, whereas an additional 22 were PCR positive in whole blood only. All 36 samples from six patients without signs of aspergillosis were negative in both assays. We conclude that although plasma and whole blood spiked with Aspergillus conidia showed an identical lower detection limit (10 CFU), the sensitivity of plasma PCR was lower than that of PCR performed on whole blood samples.