Activation of mammalian target of rapamycin signaling promotes cell cycle progression and protects cells from apoptosis in mantle cell lymphoma

Mantle cell lymphoma (MCL) is characterized by the t(11;14) and cyclin D1 overexpression. However, additional molecular events are most likely required for oncogenesis, possibly through cell cycle and apoptosis deregulation. We hypothesized that mammalian target of rapamycin (mTOR) is activated in MCL and contributes to tumor proliferation and survival. In MCL cell lines, pharmacological inhibition of the phosphoinositide 3-kinase/AKT pathway was associated with decreased phosphorylation (activation) of mTOR and its downstream targets phosphorylated (p)-4E-BP1, p-p70S6 kinase, and p-ribosomal protein S6, resulting in apoptosis and cell cycle arrest. These changes were associated with down-regulation of cyclin D1 and the anti-apoptotic proteins cFLIP, BCL-XL, and MCL-1. Furthermore, silencing of mTOR expression using mTOR-specific short interfering RNA decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis. Silencing of eukaryotic initiation factor (eIF4E), a downstream effector of mTOR, recapitulated these results. We also assessed mTOR signaling in MCL tumors using immunohistochemical methods and a tissue microarray: 10 of 30 (33%) expressed Ser473p-AKT, 13 of 21 (62%) Ser2448p-mTOR, 22 of 22 (100%) p-p70S6K, and 5 of 20 (25%) p-ribosomal protein S6. Total eIF4E binding protein 1 and eukaryotic initiation factor 4E were expressed in 13 of 14 (93%) and 16 of 29 (55%) MCL tumors, respectively. These findings suggest that the mTOR signaling pathway is activated and may contribute to cell cycle progression and tumor cell survival in MCL.     

Fatigue resistance during high-intensity intermittent exercise from childhood to adulthood in males and females

This study examined the maturation pattern of fatigue resistance (FR) from childhood to adulthood in females and males during high-intensity intermittent exercise and compared FR between females and males in childhood and adolescence. Thirty males (boys 11.3 ± 0.5 years, teen-males 14.7 ± 0.3 years, men 24.0 ± 2.1 years) and 30 females (girls 10.9 ± 0.6 years, teen-females 14.4 ± 0.7 years, women 25.2 ± 1.4) participated in this study. They performed high-intensity intermittent exercise (4 × 18 maximal knee flexions and extensions with 1-min rest) on an isokinetic dynamometer at 120°s⁻¹. Peak torque of flexors (PTFL) and extensors (PTEX), and total work (TW) were measured. FR was calculated as % of PTEX, PTFL, and TW in 4th versus 1st set. FR was greater (P < 0.05) in boys versus teen-males and men, and in teen-males versus men. In females, FR was greater (P < 0.05) in girls versus teen-females and women, but not different between teen-females and women. FR was not different in boys versus girls and in teen-males versus teen-females. FR for PTFL, PTEX, and TW correlated negatively (P < 0.001) with the respective peak values (r = −0.68 to −0.84), and FR for TW with peak lactate (r = −0.58 to −0.69). In addition, age correlated (P < 0.01) with FR for males (r = −0.75) and females (r = −0.55). In conclusion, FR during high-intensity intermittent exercise undergoes a gradual decline from childhood to adulthood in males, while in females the adult profile establishes at mid-puberty (14–15 years). The maturation profile of FR in males and females during development appears to reflect the maturation profiles of peak torque, short-term muscle power, and lactate concentration after exercise. T. Tsirini and A. Zafeiridis contributed equally to this work.     

Bilirubin levels predict renal cortical changes in jaundiced neonates with urinary tract infection

Background  This study was undertaken to determine the incidence of urinary tract infection (UTI) and the frequency of anatomical abnormalities in newborns with unexplained jaundice and to find out if there is any correlation between bilirubin level and renal damage. Methods  We studied 462 full-term neonates for UTI. They were aged 3–25 days, with either high (>10 mg/dL) or prolonged (>10 days) hyperbilirubinemia, with or without manifestations such as fever, vomiting, diarrhea, poor feeding, lethargy, and irritability. Neonates positive for UTI were further investigated with ultrasound, cystourethrography, and acute phase renal scintigraphy with technetium-99m dimercaptosuccinate acid (DMSA). Results  Thirty neonates (6.5%) were found to have UTI. Twenty-eight of them had indirect hyperbilirubinemia and two had direct hyperbilirubinemia, with total bilirubin levels of 11.8–20.1 mg/dL. None of the neonates was found to have jaundice because of other reasons such as infection. Vesicoureteral reflux was found in 5 neonates and one of them was combined with hydronephrosis. Renal scintigraphy with technetium-99m DMSA showed renal cortex changes in 14 (46.7%) of the 30 neonates with UTI. These 14 neonates also had increased levels of bilirubin in comparison to those with normal findings of DMSA. Conclusions  The incidence of UTI in uncomplicated neonatal jaundice is relatively high. Anatomical abnormalities of the urinary tract are not rare in infected children. Increased bilirubin levels are related to pathological findings in renal scintigraphy.     

Containment of an outbreak of KPC-3-producing Klebsiella pneumoniae in Italy

From March 2009 to May 2009, 24 carbapenem-resistant Klebsiella pneumoniae isolates were recovered from 16 patients hospitalized in an Italian intensive care unit (ICU). All isolates contained KPC-3 carbapenemase and belonged to a single pulsed-field gel electrophoresis (PFGE) clone of multilocus sequence type 258 (designated as ST258). A multimodal infection control program was put into effect, and the spread of the KPC-3-producing K. pneumoniae clone was ultimately controlled without closing the ICU to new admissions. Reinforced infection control measures and strict monitoring of the staff adherence were necessary for the control of the outbreak.     

Angiogenesis in rheumatoid arthritis: a disease specific process or a common response to chronic inflammation?

Angiogenesis is the formation of new blood vessels from existing vessels. During RA new blood vessels can maintain the chronic inflammatory state by transporting inflammatory cells to the site of inflammation and supplying nutrients and oxygen to the proliferating inflamed tissue. The increased endothelial surface area also creates an enormous capacity for the production of cytokines, adhesion molecules, and other inflammatory stimuli, simultaneously the propagation of new vessels in the synovial membrane allows the invasion of this tissue supporting the active infiltration of synovial membrane into cartilage and resulting in erosions and destruction of the cartilage. This angiogenic phenotype is promoted by several pro-angiogenic molecules, the most potent of which is vascular endothelial growth factor (VEGF). Although angiogenesis is recognized as a key event in the formation and maintenance the infiltration of synovial membrane during RA, it is unclear whether angiogenesis should be considered a specific feature of the disease or a common inflammation driven process. However the emergence of biological therapies, such as anti TNF blockade, has suggested that there are features of the inflammatory response that are not general but contextual to the specificity of the tissue where inflammation occurs, and point out the relevant role of tissue-resident stromal cells in determining the site at which inflammation occurs and the specific features of chronic inflammation such as that occurs in RA.