Complex oncogene dependence in microRNA-125a–induced myeloproliferative neoplasms

Deregulation of microRNA (miRNA) expression can lead to cancer initiation and progression. However, limited information exists on the function of miRNAs in cancer maintenance. We examined these issues in the case of myeloproliferative diseases and neoplasms (MPN), a collection of hematopoietic neoplasms regarded as preleukemic, thereby representing early neoplastic states. We report here that microRNA-125a (miR-125a)–induced MPN display a complex manner of oncogene dependence. Following a gain-of-function genomics screen, we overexpressed candidate miR-125a in vivo, which led to phenotypes consistent with an atypical MPN characterized by leukocytosis, monocytosis, splenomegaly, and progressive anemia. The diseased MPN state could be recapitulated in a doxycycline-inducible mouse model. Upon doxycycline withdrawal, the primary MPN phenotypes rapidly resolved after the discontinuation of miR-125a overexpression. However, reinduction of miR-125a led to complex phenotypes, with some animals rapidly developing lethal anemia with extensive damages in the spleen. Forced expression of miR-125a resulted in elevated cellular tyrosine phosphorylation and hypersensitivity toward hematopoietic cytokines. Furthermore, we demonstrate that miR-125a targets multiple protein phosphatases. Our data demonstrate that miR-125a–induced MPN is addicted to its sustained overexpression, and highlight the complex nature of oncogenic miRNA dependence in an early neoplastic state.     

Dimensional reduction for a Bayesian filter

An adaptive strategy is proposed for reducing the number of unknowns in the calculation of a proposal distribution in a sequential Monte Carlo implementation of a Bayesian filter for nonlinear dynamics. The idea is to solve only in directions in which the dynamics is expanding, found adaptively; this strategy is suggested by earlier work on optimal prediction. The construction should be of value in data assimilation, for example, in geophysical fluid dynamics.     

Nontuberculous mycobacterial disease in northern Australia: a case series and review of the literature.

We performed a retrospective/prospective review of all cases of disease due to nontuberculous mycobacteria (NTM) reported in the Northern Territory, Australia, during the period 1989-1997. Fifty-eight cases were reported, with an average yearly incidence of 3.9 cases per 100,000 persons. The number increased significantly for the second half of the study period (39 vs. 19 cases; P<.02). The yearly incidence of pulmonary Mycobacterium avium/Mycobacterium intracellulare complex (MAC) disease not associated with human immunodeficiency virus (HIV) infection was 2.1 cases per 100,000 population. MAC was the most common isolate (78%) and pulmonary disease the most frequent clinical presentation (62%). Disease due to NTM or MAC was not found more commonly in rural areas. Significant risks for non-HIV-associated pulmonary MAC disease included male sex (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0-4.5) and age >50 years (OR, 26.5; 95% CI, 10.9-67.3), but aboriginal people appeared underrepresented (OR, 0.77; 95% CI, 0.30-1.87). Mycobacterium tuberculosis was almost 5 times more likely than NTM to be the cause of non-HIV-associated mycobacterial pulmonary disease (153 vs. 32 cases; OR, 4.79; 95% CI, 3.22-7.14). Mycobacterial lymphadenitis in aboriginal children was more likely to be tuberculous than nontuberculous (OR, 6.5; 95% CI, 1.4-41.7), but not in nonaboriginal children (OR, 1.0). With treatment, 66% of the cases of non-HIV-associated pulmonary MAC disease had favorable outcomes, and 7% of patients had progressive fatal disease. Outcomes of therapy for lymphadenitis and skin/soft-tissue disease were excellent, but those of HIV-associated disseminated MAC disease were poor.     

Polymyositis with cytochrome C oxidase negative fibers—a pathological and clinical challenge

Polymyositis (PM) with cytochrome C oxidase negative fibers also referred to as PM with mitochondrial pathology (PM-Mito) is characterized by the symptoms of inclusion body myositis (IBM) and by the myopathological findings of PM except for an increase of muscle fibers with insufficient mitochondrial cytochrome C oxidase activity. Few PM-Mito cases are published; mitochondrial ultrastructure has not been studied in these patients. We report 2 PM-Mito patients with later onset than usually seen in IBM and poor responsiveness to glucocorticoids. Electron microscopy of muscle fibers showed irregular mitochondrial ultrastructure. Sjögren syndrome related antinuclear antibodies (Anti-Ro and Anti-La) were found in one of the two patients but the typical clinical symptoms of Sjögren syndrome such as xerostomia and keratoconjunctivitis were absent in this patient. Taken together, our observations, viewed in conjunction with the current literature, suggest that PM-Mito is an underdiagnosed disease with a multifactorial pathogenesis that should be elucidated in further studies. We want to encourage clinicians and pathologists to consider the possibility of PM-Mito in patients with atypical PM or sIBM.     

Detection of pancreatic metastases by EUS-guided fine-needle aspiration

BACKGROUND: Metastases to the pancreas are usually found incidentally. Tissue diagnosis is imperative because imaging alone is incapable of differentiating them from primary pancreatic tumors. This study tested whether it is possible to differentiate metastases from other focal pancreatic lesions by using EUS-guided fine-needle aspiration (EUS-FNA) for cytodiagnosis. METHODS: One hundred fourteen consecutive patients (mean age 61 years) with focal pancreatic masses, detected on CT, underwent EUS-FNA by using a linear-array echoendoscope and 22-gauge needles. RESULTS: Adequate specimens were obtained from 112 lesions. Carcinomas were identified in 68 cases (60.7%), 56 (50%) of pancreatic origin and 12 (10.7%) from distant primary tumors. The metastases were all located in the head and body of the pancreas and measured 1.8 to 4.0 cm. The echo-texture was heterogeneous or hypoechoic in all cases and resembled that of primary tumors. Six of the 12 patients with metastatic disease had a prior diagnosis of cancer (breast, 3; renal cell, 2; salivary gland, 1), 4 of them with a recurrence and 2 with a second carcinoma metastasizing to the pancreas. Six patients without a prior diagnosis of cancer had metastases from renal cell, colonic, ovarian, and esophageal carcinomas; one metastasis was from an unknown primary and another was from a malignant lymphoma. These findings influenced the therapeutic strategy in 8 patients who underwent nonsurgical palliation. There were no complications. CONCLUSIONS: Pancreatic metastasis is an important cause of focal pancreatic lesions, but the EUS features are not diagnostic. Simultaneous EUS-FNA allows cytodiagnosis and can have a decisive influence on the selection of appropriate therapeutic strategies.     

Cytotoxicity,Phytochemical Analysis and Antioxidant Activity of Crude Extracts from Rhizomes of Elephantorrhiza Elephantina and Pentanisia Prunelloides

Background

Elephantorrhiza elephantina (Ee) and Pentanisia prunelloides (Pp) are two medicinal plants which are widely used to remedy various ailments including diarrhoea, dysentery, inflammation, fever, rheumatism, heartburn, tuberculosis, haemorrhoids, skin diseases, perforated peptic ulcers and sore joints in southern Africa (South Africa, Swaziland, Botswana and Zimbabwe). The following study was conducted to explore the in vitro cytotoxicity, antioxidant properties and phytochemical profile of the two medicinal plants.

Materials and Methods

The cytotoxicity of the aqueous and methanol extracts and fractions of both species was studied using the brine shrimp lethality tests (BST) for the first time.

Results

The results demonstrated that the lethality (LC₅₀) for crude extracts for both plants ranged between 1.8 and 5.8 ppm and was relatively greater than that for the methanol, ethyl acetate and chloroform fractions of the extracts which ranged between 2.1 ppm and 27 ppm. This suggested that crude extracts were more potent than their respective fractions, further explaining that the different fractions of phytochemicals in these plant species work jointly (in synergy) to exert their therapeutic efficacy. Both aqueous and methanol extracts of the two medicinal plants demonstrated a high degree of antioxidant capacity against the DPPH radical with the Duh and Yen inhibition percentage ranging between 4.5% and 72%. Phytochemical studies of the rhizome extracts showed that the major compounds present include flavonoids, tannins, anthocyanidins, anthraquinones, triterpenoids (oleanolic acid), the steroidal saponin Diosgenin, the sugars, rhamnose, glucuronic acid, Arabinose and hexoses.

Conclusion

This is the first report of the detection and isolation of diosgenin and oleanolic acid from the rhizome extracts of Ee and Pp. All structures were determined using spectroscopic/spectrometric techniques (1H NMR and 13C and LC-ESI-MS) and by comparison with literature data.     

Just noticeable difference in perception of physical exertion during cycle exercise in young adult men and women

The purpose of this investigation was to describe the just noticeable difference (JND) in perceived exertion during cycle exercise. Males (n = 20) and females (n = 26) (21.4 ± 3.1 year) performed load-incremented cycle exercise to peak intensity. At the end of each minute, subjects rated their overall-body perceived exertion using the OMNI (0–10) rating of perceived exertion (RPE) scale. Individual regression derived the power output (PO) corresponding to RPE 5. This PO served as the standard stimulus (SS). On a separate occasion, four 5-min cycling bouts were performed with 5 min rest between bouts. During bouts 1 and 3 subjects cycled at the SS. During bouts 2 and 4 subjects adjusted the resistance to achieve a level of exertion just noticeably above/below the SS. The difference in final 30-s oxygen consumption (VO₂) and PO between each JND bout and the previous SS were the above (JND-A) and below (JND-B) perceived exertion JNDs. JND-A and JND-B were compared between genders and between subjects exhibiting lower versus higher ventilatory threshold (VT) and VO_2PEAK within genders for VO₂ (l·min^?1, %VO_2PEAK) and PO (W, %SS). JND-B was significantly (P < 0.05) greater than JND-A for VO₂ and PO, when expressed in absolute (l·min^?1, W) and relative units (%VO_2PEAK, %SS). Males exhibited greater JND values than females in absolute, but not relative, units. Subjects with lower and higher VT and VO_2PEAK exhibited similar JND values. The JND can serve as an effective tool to measure perceptual acuity and to determine individual ability to self-regulate prescribed exercise intensities.     

A substance P (neurokinin-1) receptor mutant carboxyl-terminally truncated to resemble a naturally occurring receptor isoform displays enhanced responsiveness and resistance to desensitization

Two isoforms of the substance P (SP) receptor, differing in the length of the cytoplasmic carboxyl-terminus by ≈8 kDa, have been detected previously in rat salivary glands and other tissues. The binding and functional properties of these two isoforms have been investigated using full-length (407 amino acids) and carboxyl-terminally truncated (324 amino acids) rat SP receptors transfected stably into Chinese hamster ovary cells. Both the full-length and the truncated receptor bound radiolabeled SP with a similar K_d (≈0.1 nM). The average number of high affinity SP binding sites per cell was 1.0 × 10⁵ and 0.3 × 10⁵ for the full-length and the truncated SP receptor, respectively. In both cell lines, SP induced a rapid but transient increase in cytosolic calcium concentration ([Ca²⁺]_i), which consisted of the release of Ca²⁺ from intracellular stores and the influx of extracellular Ca²⁺. Both components are dependent on phospholipase C activation. Although the full-length and the truncated receptor utilize the same calcium pathways, they differ in their EC₅₀ values (0.28 nM for the full-length; 0.07 nM for the truncated). These differences in responsiveness may be related to the observed differences in receptor desensitization. The truncated receptor, in contrast to the full-length receptor, does not undergo rapid and long-lasting desensitization. Cells possessing the short isoform of the SP receptor would thus be expected to exhibit a prolonged responsiveness.     

Close association between valvar heart disease and central nervous system manifestations in the antiphospholipid syndrome

BACKGROUND: Heart valves lesions and central nervous system involvement are among the most common manifestations of the antiphospholipid syndrome (APS). OBJECTIVE: To evaluate possible interrelations between these manifestations in a large group of APS patients. METHODS: 284 APS patients were evaluated retrospectively, 159 of whom had primary APS. Cardiac-CNS associations were determined for the entire study population, and for subgroups of patients with primary APS or APS associated with systemic lupus erythematosus (SLE). RESULTS: Significant associations where found between cardiac vegetations and epilepsy (p < 0.02), and between cardiac valve thickening or dysfunction and migraine (p = 0.002). Borderline association was found between valvar vegetations and migraine (p = 0.09). A significant association was also found between all valvar lesions and stroke or transient ischaemic attacks. Subanalyses showed that patients with primary APS had significant associations between cardiac valve pathology and all CNS manifestations, while patients with APS associated with SLE had no such associations. CONCLUSIONS: The study suggests potential differences in biological behaviour between primary APS and APS associated with SLE. The presence of cardiac valve pathology may be a risk factor for several types of CNS involvement in PAPS.