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This study provides the first quantification of buyers' role in the outcome of R&D procurement contracts. We combine together four data sources on US federal R&D contracts, follow-on patented inventions, federal public workforce characteristics, and perception of their work environment. By exploiting the observability of deaths of federal employees, we find that managers' death events negatively affect innovation outcomes: a 1% increase in the share of relevant public officer deaths causes a decline of 32.3% of patents per contract, 20.5% patent citations per contract, and 34.3% patent claims per contract. These effects are driven by the deaths occurring in the 6 months before the contract is awarded, thereby indicating the relevance of the design and award stage relative to ex post contract monitoring. Lower levels of self-reported within-office cooperation also negatively impact R&D outcomes., (© 2021 The Authors. Journal of Economics & Management Strategy published by Wiley Periodicals LLC.)

The U.S. government invests more than $50 billion per year in R&D procurement but we know little about the outcomes of these investments. We have traced all the patents arising from government funding since the year 2000. About 1.5 percent of all R&D procurement contracts have led to at least one patent for a total of about 13,000 patents. However, contracts connected to patents account for 36 per cent of overall contract value. The gestation lag from the signing date of the contract to the patent filing is on average 33 months and does not depend on the type of R&D performed. Patents that are produced faster also seem to be more valuable. We find strong decreasing returns to contract size. Conditional on generating at least one patent, a 1-percent increase in the size of an R&D contract is associated with 0.12 percent more patents., Competing Interests: The authors have declared that no competing interests exist.

Goals: To investigate the possible use of Lactobacillus strains in the prophylaxis and/or adjuvant therapy of acute vulvovaginal candidiasis and other vaginal infections sustained by Candida yeasts., Background: The incidence of Candida infections has substantially increased in recent years. Treatment of vaginal infections with lactobacilli has a long tradition, starting with Döderlein's description of the vaginal microbiota., Materials and Methods: We assessed the activity of serially diluted fluconazole and miconazole (from 3 ng/mL to 1 mg/mL) against Candida strains. Serial dilutions of the azoles were prepared in Sabouraud Dextrose Broth in the presence of Candida strains. Broths were incubated under aerobic condition at 30°C, and the optical density was measured at 560 nm. Minimum inhibitory concentration was defined as the lowest concentration of the antibiotic that completely inhibited visible growth., Results: An evident resistance to the azoles used was recorded for all species of Candida, with the exception of Candida parapsilosis. For this species, a minimum inhibitory concentration ≤1 mg/mL was obtained, thus confirming the slight sensitivity to fluconazole and miconazole.All Lactobacillus strains tested, namely LF5, LF09, LF10, and LF11, have the ability to significantly inhibit the growth of the five species of Candida of at least 4 logarithms. Furthermore, the best result obtained with miconazole on C. parapsilosis is still 2 logarithms lower., Conclusions: The use of beneficial bacteria, especially lactobacilli, could be regarded as a good alternative for the prevention and treatment of Candida infections.

Background: Oxalate is the salt-forming ion of oxalic acid and can generate oxalate salts combining with various cations, such as sodium, potassium, magnesium, and calcium. Approximately 75% of all kidney stones are composed primarily of calcium oxalate (CaOx) and hyperoxaluria, a condition involving high urinary oxalate concentration, is considered a primary risk factor for kidney stone formation, known as nephrolithiasis. Current therapeutic strategies often fail in their compliance or effectiveness, and CaOx stone recurrence is still common. After an initial stone, there is a 50% chance of forming a second stone within 7 years if the condition is left untreated. The potential therapeutic application of some probiotics, mainly lactobacilli and bifidobacteria, in reducing hyperoxaluria in vivo through intestinal oxalate degrading activity is compelling and initial reports are promising. This study was undertaken to screen different Lactobacillus and Bifidobacterium strains for their capacity to degrade oxalate in vitro using reverse-phase high-performance liquid chromatography (HPLC)., Methods: The oxalate-degrading activity of 13 lactobacilli and 5 bifidobacteria was tested using a novel HPLC method after growth in a broth culture added with 10 mM ammonium oxalate. Experiments were repeated 3 times. Oxalobacter formigenes (DSM 4420) was used as positive reference to validate HPLC oxalate-degrading capability assays., Results: Lactobacillus strains were more efficient than bifidobacteria in degrading oxalates. L. paracasei LPC09 (DSM 24243) gave the best result, as 68.5% of ammonium oxalate was converted at the end of incubation, whereas the following best converters belong to the L. gasseri and L. acidophilus species. The relatively low conversion rate observed for most bifidobacteria can probably be attributed to intrinsic oxalate toxicity toward this genus., Conclusions: Humans lack the enzymes needed to directly metabolise oxalate, and this potentially toxic compound is, therefore, managed using alternative pathways. As oxalate-degrading bacteria are present in the endogenous microbiota of the human intestine, although with significant individual differences, it is possible to hypothesise that the administration of selected oxalate-degrading probiotics could be an alternative and innovative approach to reducing the intestinal absorption of oxalate and the resulting urinary excretion.

Epsins are endocytic adaptors with putative functions in general aspects of clathrin-mediated endocytosis as well as in the internalization of specific membrane proteins. We have now tested the role of the ubiquitously expressed epsin genes, Epn1 and Epn2, by a genetic approach in mice. While either gene is dispensable for life, their combined inactivation results in embryonic lethality at E9.5-E10, i.e., at the beginning of organogenesis. Consistent with studies in Drosophila, where epsin endocytic function was linked to Notch activation, developmental defects observed in epsin 1/2 double knockout (DKO) embryos recapitulated those produced by a global impairment of Notch signaling. Accordingly, expression of Notch primary target genes was severely reduced in DKO embryos. However, housekeeping forms of clathrin-mediated endocytosis were not impaired in cells derived from these embryos. These findings support a role of epsin as a specialized endocytic adaptor, with a critical role in the activation of Notch signaling in mammals.

Calcium (Ca2+) regulated secretion/exocytosis is a key mechanism for cell-cell communication. Neurotransmission and hormone release are the most studied and the best characterized of all secretion systems so far. Here, some dynamic aspects of secretory vesicle trafficking will be briefly reviewed with special emphasis on the differences between synaptic vesicle and dense-core vesicle turnover.

Conjugation of ubiquitin to proteins is a well-established signal to regulate an ever expanding range of cellular processes. Here, we discuss recent findings that deeply link ubiquitin signaling to synaptic activity.

Neuroblastoma is the most common type of cancer in infants. In children this tumor is particularly aggressive; despite various new therapeutic approaches, it is associated with poor prognosis. Given the importance of endosomal-lysosomal proteolysis in cellular metabolism, we hypothesized that inhibition of lysosomal protease would impact negatively on neuroblastoma cell survival. Treatment with E-64 or CA074Me (2 specific inhibitors of cathepsin B) or with pepstatin A (a specific inhibitor of cathepsin D) was cytotoxic for 2 neuroblastoma cell lines having different degrees of malignancy. Cell death was associated with condensation and fragmentation of chromatin and externalization of plasma membrane phosphatidylserine, 2 hallmarks of apoptosis. Concomitant inhibition of the caspase cascade protected neuroblastoma cells from cathepsin inhibitor-induced cytotoxicity. These data indicate that prolonged inhibition of the lysosomal proteolytic pathway is incompatible with cell survival, leading to apoptosis of neuroblastoma cells, and that the cathepsin-mediated and caspase-mediated proteolytic systems are connected and cooperate in the regulation of such an event. Since modern antitumor chemotherapy is aimed at restoring the normal rate of apoptosis in neoplastic tissues, the demonstration that endosomal-lysosomal cathepsins are involved in this process may constitute a basis for novel strategies that include cathepsin inhibitors in the therapeutic regimen., (Copyright 2001 Wiley-Liss, Inc.)

The expression of different protein kinase C (PKC) isoenzymes has been shown to vary with proliferation rates, differentiation or apoptosis in normal colon crypts. In addition, the activity of some PKC isoenzymes appears to be reduced in colorectal cancer. The aim of the present work was to determine whether modulation of PKC expression would affect the susceptibility of a p53-defective colon carcinoma cell line to different apoptotic treatments. HT-29 cells exhibited sensitivity to paclitaxel (Taxol) and tumor necrosis factor alpha (TNFalpha) in a dose- and time-dependent manner but were relatively resistant to etoposide. Inhibition of PKC activity augmented the susceptibility of HT-29 cells to apoptosis, and phorbol ester induction of PKC reduced such susceptibility. Transfected HT-29(PKC) cells, hyper-expressing the beta1 isoform of PKC, were less sensitive to TNFalpha and paclitaxel than the normal counterpart. The present data 1) indicate that the expression of PKC influences the susceptibility of HT-29 colon cancer cells to apoptotic drugs apparently regardless of their mechanism of action, and 2) suggest paclitaxel as a potential candidate for the treatment of colon cancer, possibly in association with inhibitors of PKC (alpha and beta) at doses not cytotoxic per se., (Copyright 2001 Wiley-Liss, Inc.)

The expression, processing, and intracellular localization of cathepsin D (CD), an endosomal-lysosomal protease involved in malignancy, were studied in rat embryo fibroblasts transformed with an active mutant of c-Ha-ras oncogene. The pattern of the processed molecular forms of CD, comprising two single-chain mature forms of 45 and 43 kDa and two double-chain mature forms of 34 + 9 kDa and 30 + 14 kDa, expressed by the parental cell line was similar to that found in normal rat liver cells. By contrast, in the ras-transfected counterpart this pattern was profoundly altered in that the 45 kDa species was much less represented and the 30 + 14 kDa species virtually absent. In both untransformed and ras-transformed cells the conversion of proCD into mature forms was not inhibited by ammonium chloride, which is known to increase the intravacuolar pH of post-Golgi compartments. Yet, this drug induced the accumulation of the 43 and 45 kDa molecular forms of mature CD in ras-transformed cells and of the 34 kDa molecule in untransformed cells. As compared to controls, in ras-transformed fibroblasts vacuolar compartments containing CD were reduced in number and mostly located toward the periphery of the cell. This contrasted with the perinuclear distribution of CD-positive granules in untransformed cells. Serum deprivation did not affect the growth, nor the intra- and extracellular accumulation of CD activity in ras-transformed cultures, while it blocked the growth and strongly stimulated the accumulation of CD in the medium in cultures of control fibroblasts. Altogether these data are indicative for a crucial role of ras GTPase in the regulation of the transport between post-Golgi organelles.

Choroid plexus carcinoma (CPC) is a rare tumor with usually severe prognosis, whose optimal treatment has not yet been established. The exact role of complete surgical resection, chemotherapy, and radiotherapy has been debated but not clarified. We report one girl with CPC diagnosed at age 3 months and apparently cured with minimal surgical resection, chemotherapy, and delayed irradiation. At the age of 8 years, she is well, with minor psychomotor retardation and growth hormone deficiency as the only sequelae.

Langerhans cell histiocytosis (LCH) is a non-malignant disorder, whether localized or disseminated, and usually has a favourable prognosis. A possible relationship between LCH and neoplastic diseases has not been assessed up to now even if a few cases have been recorded. We report two new cases of acute leukemia in children with LCH. The first child had acute lymphoblastic leukemia after untreated LCH; the second developed acute promyelocytic leukemia after LCH treated with vinblastine and etoposide. To our knowledge, this is the first case of secondary leukemia after exposure to an epipodophyllotoxin derivative in a child with benign disease. Cooperative studies of large numbers of LCH patients are needed to evaluate a possible association between LCH and acute leukemia, and to identify common risk factors or predisposing agents if such be present.

Adrenocortical carcinoma (ACC) in childhood is a rare tumor with high fatality rate. Available reports provide event free survival rates ranging between 10 to 50%. Optimal treatment has not yet been established; surgery plays a major role, and the value of adjuvant chemotherapy needs to be evaluated further, especially in children who develop recurrent disease and those with metastases at diagnosis. Optimal therapy of ACC has not been established. Surgery has been curative after complete tumor resection. Children with inoperable, recurrent and metastatic ACC have been treated with O,P'DDD, with response rates ranging from 10 to 60% in different series [7,11-20]. Radiotherapy [21] and other anti-cancer drugs have been used [4-22] but their efficacy has not been established. Combination chemotherapy containing oncovin, cisPlatinum, epipodophyllotoxin and cyclophosphamide (OPEC) produced regression of metastatic ACC in a 5-year-old male [23]. We report one girl with relapsed disseminated ACC who showed good, even if temporary, control of the disease, with disappearance of lung, liver and spleen metastases, and marked reduction of the adrenal mass, following combined chemotherapy according to the "eight-drugs-in-one-day" protocol.

Background: Many of the drugs used in the treatment of acute lymphoblastic leukemia in children may induce modifications in different organs and functions. Following the observation of a recurrent, mild delay in the prothrombin time in ALL children during maintenance chemotherapy, we explored the main parameters of the clotting function., Methods: 17 children with acute lymphoblastic leukemia were studied during maintenance chemotherapy for clotting function screening evaluation; 15 healthy children, matched for age and sex, were used as controls., Results: A uniform pattern of slight prolongation of the prothrombin time with significantly reduced levels of factors VII, IX, and a trend toward reduced activity of factor X was observed in the absence of any demonstrable anticoagulant factor., Conclusions: Antileukemic maintenance chemotherapy is associated with a subclinical modification of the clotting parameters that is not responsible for hemorrhagic diathesis. Long-term administration of anti-metabolites (6-mercaptopurine and methotrexate) could be responsible for this reversible impairment.

The behaviour of three complement components (C3, C4 and C3 activator), alpha 1, alpha 2, IgA, IgG, IgM, total proteins, and gamma globulins was followed 114 patients at the C.T.O. Turin, Burns Centre with burns covering from 15% to over 70% of the body surface. Forty-two died within a relatively short time. In the remaining 72, the parameters were studied almost daily for over 30 days, or even until a final cure was obtained. The complement data and, more particularly, the distinct increased in alpha-globulins made it clear that burns can be acute inflammations. In addition, initial immune depression is followed by a prompt response of the complement system (responsible for aspecific immunity). That this change is vital in the progress of the disease may be deduced from the fact that complement component levels were constantly below normal in the patients who died.

Bearing in mind the complexity of the topic and its variability owing to the progress made in antibiotic management, and the development of many concepts concerning the pathogenesis and biochemistry of major burns, the already massive literature is supplemented by the addition of relatively recent data to enable comparisons to be made with regard to the quality and frequency of isolation of the bacterial flora observed in such patients, and above all their sensitivity to currently employed antibiotics. The investigation was conducted on patients admitted to the Turin CTO Major Burns Centre between 1972 and 1977. Initially (1972-1975), a microbiological examination was made of purulent secretions from wounds. Subsequently, management was prevalently directed to the early excision of injured surfaces, and attention was therefore directed to the indwelling venous catheters used in treatment and parenteral alimentation. In cases examined in parallel, moreover, there was often a substantial similarity between wound and catheter flora, and when only one species was present in the wounds, the catheter was often sterile. Furthermore, numerous data were collected from antibiograms relating to the most frequently encountered micro-organisms. These usually displayed wide resistance spectra, especially with respect to the most commonly used of historically oldest antibiotics, whereas their resistance to those recently introduced was generally lower. The question of provenance (from the patient himself, the hospital or its medical and paramedical staff) is also examined. Reference is made to a point that has recently become important in the treatment of burns, namely the ascertainment of the degree of contamination not only on the surface, but also in the immediate sub-surface of the lesions, so as to permit a suitable excision of the eschar and skin transplantation. When a sufficient number of findings exist to support this new concept, it will certainly give rise to further studies and research aimed at bringing new, important data to this so rich and multiform topic.