The oriental fruitfly Bactrocera dorsalis s.s. in East Asia: disentangling the different forces promoting the invasion and shaping the genetic make-up of populations.

The Oriental fruit fly, Bactrocera dorsalis sensu stricto, is one of the most economically destructive pests of fruits and vegetables especially in East Asia. Based on its phytophagous life style, this species dispersed with the diffusion and implementation of agriculture, while globalization allowed it to establish adventive populations in different tropical and subtropical areas of the world. We used nine SSR loci over twelve samples collected across East Asia, i.e. an area that, in relatively few years, has become a theatre of intensive agriculture and a lively fruit trade. Our aim is to disentangle the different forces that have affected the invasion pattern and shaped the genetic make-up of populations of this fruit fly. Our data suggest that the considered samples probably represent well established populations in terms of genetic variability and population structuring. The human influence on the genetic shape of populations and diffusion is evident, but factors such as breeding/habitat size and life history traits of the species may have determined the post introduction phases and expansion. In East Asia the origin of diffusion can most probably be allocated in the oriental coastal provinces of China, from where this fruit fly spread into Southeast Asia. The spread of this species deserves attention for the development and implementation of risk assessment and control measures.

Extracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis.

Recent studies have shown that the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and responsiveness to immunotherapy. A question that remains unresolved is whether the ECM directly educates the immune phenotypes seen in tumors. Here, we identify a tumor-associated macrophage (TAM) population associated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether the ECM was capable of generating this TAM phenotype, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissue. ECM-educated macrophages have a tissue-remodeling and immunoregulatory phenotype, inducing altered T cell marker expression and proliferation. We conclude that the tumor ECM directly educates this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.

Targeting immunoliposomes to EGFR-positive glioblastoma.

BACKGROUND: We assessed the capacity of epidermal growth factor receptor (EGFR)-targeted immunoliposomes to deliver cargo to brain tumor tissue in patients with relapsed glioblastoma harboring an EGFR amplification. We aimed to assess the tolerability and effectiveness of anti-EGFR immunoliposomes loaded with doxorubicin (anti-EGFR ILs-dox) in glioblastoma multiforme patients. PATIENTS AND METHODS: Patients with EGFR-amplified, relapsed glioblastoma were included in this phase I pharmacokinetic trial. Patients received up to four cycles of anti-EGFR ILs-dox. Twenty-four hours later, plasma and cerebrospinal fluid (CSF) samples were obtained. In addition, we also treated three patients with anti-EGFR ILs-dox before resection of their relapsed glioblastoma. Doxorubicin concentrations were measured in plasma, CSF, and tumor tissue. Safety and efficacy parameters were also obtained. RESULTS: There were no or negligible levels of doxorubicin found in the CSF demonstrating that anti-EGFR ILs-dox are not able to cross the blood-brain barrier (BBB). However, significant levels were detected in glioblastoma tissue 24 h after the application, indicating that the disruption of BBB integrity present in high-grade gliomas might enable liposome delivery into tumor tissue. No new safety issues were observed. The median progression-free survival was 1.5 months and the median overall survival was 8 months. One patient undergoing surgery had a very long remission suggesting that neoadjuvant administration may have a positive effect on outcome. CONCLUSIONS: We clearly demonstrate that anti-EGFR-immunoliposomes can be targeted to EGFR-amplified glioblastoma and cargo-in this case doxorubicin-can be delivered, although these immunoliposomes do not cross the intact BBB. (The GBM-LIPO trial was registered as NCT03603379).

Bone turnover, osteopenia and vascular calcifications in hemodialysis patients. A histomorphometric and multislice CT study.

BACKGROUND: Several classical risk factors are at the base of vascular calcifications in hemodialysis patients. Among these, according to a general opinion, also bone turnover plays a role, which, however, requires a better definition. In addition, it has been suggested that there is a relationship between primary osteoporosis and vascular calcifications. This bone biopsy-based study on a hemodialysis patient cohort is a contribution to the evaluation of these alleged relations. METHODS: This study has been carried out on a cohort of 32 patients on maintenance hemodialysis, who were subjected to transiliac bone biopsy for histomorphometric, histodynamic and bone aluminum deposit evaluation. The patients were also examined with multislice computerized tomography for quantitation of heart and coronary calcifications. RESULTS: The patients were affected by renal osteodystrophy with a wide range of bone formation rate values. A significant negative correlation was found between the rate of bone turnover and log-transformed cardiac calcification score (p < 0.003). There were also negative significant correlations between the cardiac and coronary calcification score log and trabecular number (p < 0.02 and p < 0.05, respectively), while the correlations were positive with trabecular separation (p < 0.03 and p < 0.05, respectively). However, multiregression analysis, forward method, selected only age, hemodialysis age and serum Ca as predictive variables of cardiac and coronary calcification score log, while the histomorphometric and histodynamic variables were excluded. CONCLUSIONS: In this study, in spite of the suggestive findings of the univariate statistical approach, a further multivariate analysis was indicative of a spurious association between calcification scores and both bone turnover and histomorphometric parameters of trabecular mass and connectivity. Bone turnover and trabecular mass do not appear to be prominently connected with the extent of cardiac and coronary calcifications in hemodialysis patients.

Cardiac calcifications in hemodialysis patients assessed with spiral computed tomography.

AIM: Cardiac disease is a major cause of mortality in uremic patients. The aim of this paper was to evaluate cardiac calcium content in uremic patients with multislice computed tomography (MSCT). METHODS: The study has been carried out on 120 uremic and 28 nonuremic patients affected by cardiovascular disease. Serum calcium, phosphorus, calcium-phosphate product, intact PTH were assayed. Several lipidic and nutritional parameters were measured. Calcification values obtained with the MSCT were reported in terms of Agatson scores. RESULTS: We found that the average score values in cohort on uremic was 10 times higher than in nonuremic patients (score values 3.389 vs 328). Cardiac calcification score was found to be correlated significantly to age (P=0.006), HD age (P=0.010), serum calcium (P=0.006), iPTH (P=0.004). Multiregression analysis (MRA) with the cardiac score as dependent variable selected the following variables (R(2) 0.612): age (P=0.002), HD age (P=0.010), serum cholesterol (P<0.000), triglycerides (P=0.001) and inversely HDL cholesterol (P=0.001) and non-HDL cholesterol (P=0.001) as predictive variables for cardiac score. By comparing patients with scores lower and higher than 400, the group with score <400 showed a significantly lower age (P=0.0001), HD vintage (P=0.01) and a significantly higher serum cholesterol (P=0.009), HDL cholesterol (P=0.05) and non-HDL cholesterol (P=0.05). CONCLUSIONS: The MSCT could help in identifying and stratifying high-risk patients to implement preventive strategies. The control of mineral metabolism and of lipid levels is important in prevention of arterial calcification in uremic patients.

[Can cardiovascular calcifications be prevented in chronic kidney disease?]. / E possibile prevenire i processi di calcificazione cardiovascolare nel paziente con insufficienza renale cronica?

Chronic kidney disease, with special regard to hemodialysis patients, develop frequent and widespread cardiac and vascular calcifications. In the heart calcifications are mainly located in the coronary arteries and in the valvular structures. There is a strict relation between cardiovascular mortality in CKD and the extent of cardiac and vascular calcifications. Therefore it is important to evaluate the causes of extraskeletal calcifications for the evaluation of the possibility of prevention. The importance of hyperphosphatemia, of hypercalcemia and of the increased CAxP product as a cause of cardiac calcification has been clearly underlined. However the mechanism of calcification, initially considered a physico-chemical precipitation, has been investigated with the conclusion that the process is mediated by cellular differentiation and production of factors favoring mineralization in the extracellular milieu. Increased serum phosphate levels are able to induce a transformation of vascular smooth muscle cells into osteoblast-like cells, able to produce factors known to be pro-mineralizing agents in the bone tissue. Further studies have revealed the importance of a number of inhibitors of calcification of cardiovascular structures, like Fetuin-A, MGP, Osteopontin, Osteoprotegerin. Therefore at present the calcification process of vascular tissue is considered to be linked to a balance between inducers and inhibitors of calcium-phosphate deposits. Prevention of cardiac calcifications is at present mainly based of optimal control of serum phosphate and reduction of calcium load through the use of non-calcium containing phosphate binders. Treatment with statins for prevention and treatment of atherosclerosis is also an important means of decreasing the size and number of atherosclerotic plaques, where a portion of the calcification process develops.

Lack of beta-amyloid production in M19 cells deficient in site 2 processing of the sterol regulatory element binding proteins.

The processing of the amyloid precursor protein (APP) and the sterol regulatory element binding protein show remarkable analogies. Following a first lumenal cleavage, both proteins undergo a cleavage within the transmembrane domain by enzymatic activities named gamma-secretase and S2P, respectively. We analyzed the processing of APP in the mutant Chinese hamster ovary (CHO) cell line M19 which lacks the S2P gene encoding for a putative metalloprotease. In these cells, we were not able to detect any beta-amyloid production from endogenous or transiently overexpressed APP, although the transport of APP along the secretory pathway, its processing by alpha- and beta-secretase, as well as its secretion were normal. This strongly suggests that the gamma-secretase cleavage in M19 cells is severely impaired.

Solitary metastases to the cranial vault. Report of ten cases.

BACKGROUND: Metastatic spread of tumors to the skull is quite unusual and often represents a relevant diagnostic and therapeutic problem. Skull involvement can be observed in various neoplasms of epithelial origin (rarely in other tumors) and most often responsible are lung, breast, thyroid, kidney and prostate cancers. Less frequent than multiple involvement, single cranial vault lesions are often amenable to surgical resection instead of radiotherapy alone; scope of this paper is to highlight the key points of the management of such entities, including a brief review of the pathological and radiological features of these entities. METHODS: A retrospective study has enabled us to select from our files ten cases of surgically treated solitary cranial vault metastases, with a variable follow-up ranging from 6 months to 4 years. In all the cases the operation consisted in a monobloc resection and a cranioplasty for the repair of the defect. RESULTS: We have observed no perioperative morbidity or mortality; in all the cases surgery allowed histologic confirmation and immediate relief of neurological symptoms and cosmetic impairment (when present). CONCLUSIONS: Monobloc resection of solitary cranial vault metastatic lesions is an easy made and safe procedure, to be performed in every patient except the ones in poor general conditions, which are better addressed to radiotherapy alone.

Cardiac calcium evaluation in hemodialysis patients with multisection spiral computed tomography.

AIM: The aim of this study is cardiac calcium content evaluation in hemodialysis patients by a new technique, based on ultrafast multisection CT (MTC). METHODS: The study was carried out on 30 HD patients, 14 F and 16 M, average age 57.7 +/- 13.9 years, average HD age 57.3 +/- 47.4 months. The intact PTH levels were 625.4 +/- 571 pg/mL. Serum calcium, phosphate and CaxP product were 9.75 +/- 0.84 mg/mL, 6.21 +/- 1.01 mg/dL and 60.2 +/- 10.7 mg2/dL2, respectively. RESULTS: The values obtained with the MTC technique were reported in terms of Agatson scores. Score values frankly in the pathologic range (>100) were found in 24 patients (80%). Correlation analysis has shown positive and significant correlation coefficients of the score with patients' age (p = 0.003), serum calcium (p = 0.012), CaxP (p = 0.015), iPTH (p = 0.049), and borderline, to HD age (p = 0. 06). CONCLUSION: Risk factors for cardiac calcification are mainly age, degree of hyperparathyroidism, increased CaxP and serum calcium levels. A control of calcium phosphate parameters in hemodialysis patients seems to be mandatory to avoid increased severity of coronary artery disease.

[Long-term assessment of bone loss in patients treated with GnRH agonists]. / Valutazione a lungo termine della perdita calcica ossea nelle pazienti trattate con GnRH Agonisti.

GnRH Analogues therapy of estrogen-dependent gynaecological diseases aims at suppression of physiologic ciclic ovaric function producing a hypogonadotropic condition. The first consequence of GnRH Analogues administration is hypoestrogenism; this condition permits the disease regression but, on the other, it causes a negative impact on bone metabolism particularly for prolonged therapeutic schemes (6 months). This study has evaluated the faculty of bone mass protection combining GnRH Analogues therapy with Ipriflavone that stimulates, both "in vivo" and "in vitro", Osteoblastic cells activity. The result of this study showed a significant bone loss in patients treated with GnRH Analogues only. The Ipriflavone association prevented bone loss.

Sphenoidal metastasis from prostate carcinoma. Case report and review of the literature.

A case of an uncommon sphenoidal metastasis from prostate carcinoma with cranial nerve involvement is described. Current concepts of metastatic spread of this tumor to the skull base, clinical signs and therapeutic approaches are reviewed in the light of the available literature.

The complex relationship between inflammation and lung function in severe asthma.

Asthma is a common respiratory disease affecting ∼300 million people worldwide. Airway inflammation is thought to contribute to asthma pathogenesis, but the direct relationship between inflammation and airway hyperresponsiveness (AHR) remains unclear. This study investigates the role of inflammation in a steroid-insensitive, severe allergic airway disease model and in severe asthmatics stratified by inflammatory profile. First, we used the T-helper (T(H))-17 cells adoptive transfer mouse model of asthma to induce pulmonary inflammation, which was lessened by tumor necrosis factor (TNF)-α neutralization or neutrophil depletion. Although decreased airspace inflammation following TNFα neutralization and neutrophil depletion rescued lung compliance, neither intervention improved AHR to methacholine, and tissue inflammation remained elevated when compared with control. Further, sputum samples were collected and analyzed from 41 severe asthmatics. In severe asthmatics with elevated levels of sputum neutrophils, but low levels of eosinophils, increased inflammatory markers did not correlate with worsened lung function. This subset of asthmatics also had significantly higher levels of T(H)17-related cytokines in their sputum compared with severe asthmatics with other inflammatory phenotypes. Overall, this work suggests that lung compliance may be linked with cellular inflammation in the airspace, whereas T-cell-driven AHR may be associated with tissue inflammation and other pulmonary factors.

The glucose transporter of Escherichia coli with circularly permuted domains is active in vivo and in vitro.

The bacterial phosphotransferase system (PTS) consists of two energy-coupling soluble proteins (enzyme I and HPr) and a large number of inner membrane transporters (enzymes II) that mediate concomitant phosphorylation and translocation of sugars and hexitols. The transporters consist of three functional units (IIA, IIB, IIC), which occur either as protein subunits or domains of a multidomain polypeptide. The membrane-spanning IIC domain contains the substrate binding site; IIA and IIB are phosphorylation domains that transfer phosphate from HPr to the transported sugar. The transporter complexes of the PTS are good examples for variation of design by modular assembly of domains and subunits. The domain order is IIC-IIB in the membrane subunit of the Escherichia coli glucose transporter (IICBGlc) and IIB-IIC in Salmonella typhimurium sucrose transporter (IIBCScr). The phosphorylation domain of IICBGlc was translocated from the carboxyl-terminal to the amino-terminal end of the IIC domain, and the activity of the circularly permuted form was optimized by variation of the length and the composition of the interdomain linker. IIBapCGlc with an alanine-proline-rich interdomain linker has 70% of the control specific activity after purification and reconstitution into proteoliposomes. These results indicate that the amino-terminal end of IICBGlc must be on the cytoplasmic side of the inner membrane, that membrane insertion of the IIC domain is insensitive to the modification of its amino-terminal end, and that a domain swap as it could occur by a single DNA translocation event can rapidly lead to a functional protein. However, IIB could not be substituted for by glucokinase. Fusion proteins between the IIC domain and glucokinase do not transport and phosphorylate glucose in an ATP-dependent mechanism, although the IIC moiety displays transport activity upon complementation with soluble subclonal IIB, and the glucokinase moiety retains ATP-dependent nonvectorial kinase activity. This indicates that IIC and IIB are two cooperative units and not only sequentially acting upon a common substrate, and that translocation of glucose must be conformationally coupled to the phosphorylation/dephosphorylation cycle of IIB.

Evaluation of BACTEC system for urine culture screening.

We compared urine culturing performed by the calibrated loop method with a screening system (BACTEC). A total of 852 urine specimens were examined by both the conventional loop method and the BACTEC system. With the loop method, 193 (22.6%) urine samples were positive, whereas with the BACTEC system, 185 (21.7%) were positive (sensitivity, 96.01%). At a breakpoint of 10(4) CFU/ml, eight false-negatives were detected (sensitivity, 87.09%), and at a breakpoint of 10(5) CFU/ml, four false-negatives were observed (sensitivity, 97.6%). The specificity of the BACTEC system was 100%. We propose the BACTEC method as an effective alternative to the other growth-dependent screening tests for bacteriuria.

Plasma insulin-like growth factor-1 and bone formation parameters in predialysis chronic renal failure.

Insulin-like growth factor-1 (IGF-1), produced by osteoblasts following parathormone (PTH) stimulation, is a local hormone with autocrine and paracrine functions on bone formation. To evaluate whether circulating IGF-1 is also important in stimulating bone formation, a study was carried out on 28 patients with slowly progressing nondialytic chronic renal failure. 9 patients were treated with 1,25(OH)2D3, while 19 did not receive vitamin D metabolites. In all patients a transiliac bone biopsy for histomorphometric studies was obtained, and the following determinations were made: immunoreactive PTH (iPTH), osteocalcin, alkaline phosphatase, IGF-1, serum calcium, phosphate and creatinine. Serum IGF-1 levels were similar in the two groups of patients, and higher than normal. iPTH and osteocalcin were positively correlated with serum creatinine, osteoblast surface and the eroded surface, but did not correlate with IGF-1. A negative (n.s.) relationship was found between dynamic bone parameters and circulating IGF-1, with the mineral apposition rate reaching a significant level (p less than 0.05). In conclusion, the circulating levels of IGF-1 are not correlated with bone formation parameters, thus apparently showing no role in bone turnover or dependency on bone production of the growth factor. The results may favor the hypothesis of a negative feedback control of circulating IGF-1 by suppressive signals originating from active bone metabolic units.