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KEAP1 mutations have been associated with reduced survival in lung adenocarcinoma (LUAD) patients treated with immune checkpoint inhibitors (ICIs), particularly in the presence of STK11/KRAS alterations. We hypothesized that, beyond co-occurring genomic events, clonality prediction may help identify deleterious KEAP1 mutations and their counterparts with retained sensitivity to ICIs.Beta-binomial modelling of sequencing read counts was used to infer KEAP1 clonal inactivation by combined somatic mutation and loss of heterozygosity (KEAP1 C-LOH) versus partial inactivation (KEAP1 clonal diploid-subclonal, KEAP1 CD-SC) in the MSK MetTropism cohort (N=2,550). Clonality/LOH prediction was compared to a streamlined clinical classifier that relies on variant allele frequencies (VAFs) and tumor purity (TP) (VAF/TP ratio). The impact of this classification on survival outcomes was tested in two independent cohorts of LUAD patients treated with immunotherapy (MSK/Rome N=237; DFCI N=461). Immune-related features were studied by exploiting RNA-sequencing data (TCGA) and multiplexed immunofluorescence (DFCI mIF cohort).Clonality/LOH inference in the MSK MetTropism cohort overlapped with a clinical classification model defined by the VAF/TP ratio. In the ICI-treated MSK/Rome discovery cohort, predicted KEAP1 C-LOH mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAP1 wild-type cases (PFS log-rank P=0.001; OS log-rank P0.001). Similar results were obtained in the DFCI validation cohort (PFS log-rank P=0.006; OS log-rank P=0.014). In both cohorts, we did not observe any significant difference in survival outcomes when comparing KEAP1 CD-SC and wild-type tumors. Immune deconvolution and multiplexed immunofluorescence revealed that KEAP1 C-LOH and KEAP1 CD-SC differed for immune-related features.KEAP1 C-LOH mutations are associated with an immune-excluded phenotype and worse clinical outcomes among advanced LUAD patients treated with ICIs. By contrast, survival outcomes of patients whose tumors harbored KEAP1 CD-SC mutations were similar to those with KEAP1 wild-type LUADs.

According to projects and practices that the Italian botanists and ecologists are carrying out for bringing “more nature in the city”, new insights for a factual integration between ecological perspectives and more consolidated aesthetic and agronomic approaches to the sustainable planning and management of urban green areas are provided.

In the region of Murcia, a series of watch and defensive towers were planned and built during the reign of King Philip II. These coastal buildings formed part of a more extensive network that included the entire Mediterranean coastline of Spanish dominions; in particular in this region, thirty-six defensive towers, were planned, but only twelve towers were actually built. The King commissioned the project to the Italian military engineer Giovanni Battista Antonelli and the military expert in fortifications and viceroy of Valencia and Navarre, Vespasiano Gonzaga, who starting from the year 1570 designed and built the defensive system. The aim of this network of towers was to monitor, alert and protect the coast against the raid of pirates, enabling fast communication with other towers through fires during the night or smoke plumes during the day and then to receive the necessary assistance and inform of an attack: visibility among towers was a fundamental issue. They have been active for more than two centuries and undergone to modifications and rehabilitations. The typologies of plans were several, ranging from circular, rectangular and hexagonal. At the present time, among the twelve towers built, seven have disappeared, four have been restored and only one of them remains in state of ruin, without any intervention: the Navidad tower. This heritage al risk has been chosen to be graphically documented and studied. This research is aimed at obtaining a full digital documentation of the Navidad tower through laser scanner and digital photogrammetry in order to supply a basis for its design and construction analysis, necessary for a proper restoration proposal. Likewise, this work includes the study of the watchtowers of the region, its position and its characteristics through Geographic Information Systems.

In order to calculate the incidence of hepatitis C virus (HCV) antibodies in blood donors and to verify the efficacy of the pre-donation method (testing blood samples of potential donors at least 3 months in advance of their first donation), we performed a retrospective cohort study in 1995 and in the period 1996–2000 at the blood transfusion unit in Latina (Italy). Third generation ELISA method as well as RIBA-3 were used. 5,978 donors in 1995 and 20,741 in the 1996–2000 period were analysed. The age of donors (prevalently male, 78.5%) was between 18 and 65 (median 38). A total of 110 borderline and 62 positives were found with ELISA, of which 75 borderlines and 42 positives in 1995, and the remaining in the 1996–2000 period (p > 0.5). Percentage of HCV antibodies dropped from 8.5% in 1995 to 5.45% in the 1996–2000 period. The non reactivity and undetermined status were found in 82.1 and 9.4% respectively in 1995, and 69.1 and 25.45% respectively in the 1996–2000 period. The incidence of HCV antibodies was 167.28 cases per 100,000 person-years in 1995 and 4.13 per 100,000 person-years in the 1996–2000 period, 2.5 times lower than the national one. There was a statistically significant association between dental care and RIBA positivity (RR: 2.63; p = 0.045). This study, moreover, evidences how pre-donation practices, if extended to a national basis, may be able to nullify the dangers associated with post-transfusional hepatitis and to reduce the number of false positives and of blood packs donated but either unused or destroyed.

In 1997, Congress enacted legislation to transition the Student Loan Marketing Association (Sallie Mae) from status as a government-sponsored enterprise (GSE) to a fully-private, non-federally chartered organization. The process through which this legislation was enacted will have precedential value for future legislation affecting other GSEs. This article reviews the unique context in which the Sallie Mae Privatization Act was considered and enacted. Sallie Mae was an active participant in the development of the privatization legislation, and Congress had little precedent in considering the diverse interests of stakeholders such as other entities involved in student loans, taxpayers, and Sallie Mae shareholders. Full assessment of the 1997 legislation requires a review of how the “privatizing” of Sallie Mae changes the student loan marketplace.

CSCW applications often require broadband network infrastructures able to support multipoint-to-multipoint configurations. Current B-ISDN signalling standards only provide unidirectional multicast communication. Following the principle of re-using as much as possible existing standardised protocols, multipoint-to-multipoint capability can be achieved as a mesh of correlated point-to-multipoint connections introducing some new control functionality. Control functionality foresees the invocation of suited remote operations through the generic functional protocol transport mechanism. After the description of the proposed approach to the multipoint-to-multipoint call, the paper describes the design and the implementation of a functional entity, called signalling server, capable to handle it. This paper is partially based on the results of the ACTS project AC012 MULTICUBE. It is worth highlighting that signalling server implementation is successfully running in MULTICUBE's trials.

The paper gives a general description of a software simulator designed to study the impact, in terms of protocol signalling, that multimedia services will have on B-ISDN. Object oriented techniques have been adopted to build both the simulator and the protocols to be tested. The protocols developed are able to cater for the multiparty, multimedia, multiservice aspects of the B-ISDN at the user access to the network (UNI-user network interface), and at the internal network interfaces (NNI-network node interface). As the simulator implements a representation of physical network entities, such as bearer channels and combiners/converters the actions of the protocols can be visualized and tested. The simulator can also undertake performance measurements on the operation of the protocols. The work presented in this paper is based on the results of the RACE MAGIC project.

The multimedia multiparty services, which will be introduced in the ATM based B-ISDN networks, will impose new requirements and introduce added complexity on the control protocols and software of the B-ISDN. After a survey on the evolution of the B-ISDN control protocols beyond Release 2 of ITU-T, a high level network scenario is proposed for the integration of the intelligent network (IN) into the B-ISDN. A representative example, showing the provisioning of an advanced service, is given to validate the architecture. The goal is to show how an intelligent broadband network can simplify the control of network resources and facilitate the introduction and the provisioning of advanced services.

Tacrolimus has a negative effect on the pancreatic beta islet cell, and both glucose intolerance and diabetes mellitus are well-recognized complications of tacrolimus-based immunosuppression among adult solid organ transplant recipients.To determine the association between tacrolimus and new-onset diabetes mellitus in childhood, we reviewed data on 78 pediatric heart and heart-lung/lung recipients receiving tacrolimus-based immunosuppression. Trough tacrolimus levels, fasting and random blood glucose levels, and corticosteroid requirements were reviewed. Diabetes was defined as glucose intolerance requiring long-term insulin treatment more than 30 days after transplantation.No patient had diabetes before introduction of tacrolimus. In heart-lung/lung recipients, 12 of 28 (43%) had development of diabetes at a median follow-up of 7 months (range 1 to 39). In this group diabetes developed in three of eight (38%) patients with cystic fibrosis and nine of 20 (45%) without (p = NS). In contrast, only two of 50 (4%) heart transplant recipients had development of diabetes. Of the 14 patients with diabetes, 10 had development of diabetes during augmentation of immunosuppression with pulsed corticosteroids. Tacrolimus trough levels were significantly lower in heart compared with heart-lung/lung transplant recipients (9.4 +/- 3.3 versus 15.3 +/- 0.9 ng/ml) (p0.01), and at latest follow-up significantly fewer heart transplant recipients were treated with maintenance corticosteroids (28% versus 75%; p0.01). In the heart-lung/lung group, no significant difference in tacrolimus levels was found between patients with and without diabetes, nor was there a significant difference in the average corticosteroid dose or number of pulses of corticosteroids per patient.New-onset diabetes mellitus is rare in pediatric heart transplant recipients receiving tacrolimus-based immunosuppression, but it occurs with a high incidence after pediatric heart-lung/lung transplantation and usually develops during pulsed corticosteroid therapy. However, it is currently not possible to predict which heart-lung/ lung transplant recipients will have development of this serious complication.

The case manager, like many “new professions” does not yet have a defined curriculum. We consider that the principal requisite for case managers is a proficient knowledge of assessment for the care of the elderly. Therefore, we focused a four-week teaching course for future case managers on the National Resident Assessment Instrument (RAI) of the United States and the Long-Term Care Program Application and Admission Form of British Columbia, Canada. We verified that this simple program provides students with adequate skills to become case managers.

The adequacy of caloric intake of geriatric patients in medical and surgical wards in the acute care hospital was assessed in a prospective, observational study. Fifty-one surgical and 80 medical nonterminal patients aged over 70 years underwent a multidimensional assessment on admission and a nutritional reassessment on discharge. The average daily caloric intake was also measured. Patients were divided into two groups according to whether the ratio of the actual to the needed caloric intake was inferior to 40% or not, and their differences, with regard to baseline values, were assessed. Patients whose caloric intake was inferior to 40% of the needed were older than the remaining ones (79.4 +/- 6.6 vs 76.6 +/- 4.9 years, p0.05), had higher prevalence of preadmission functional dependency (21.6% vs 15%, p0.001), lower body mass index (22.9 +/- 5.4 vs 24.8 +/- 3.9, p0.004) and higher comorbidity (coexisting diseases: 3.6 +/- 1.9 vs 2.8 +/- 1.6, p0.02) on admission. In conclusion, a simple assessment on admission allows targeting geriatric patients at risk for in-hospital starvation. No difference exists between surgical and medical wards in the quality of nutritional support.

Mechanical circulatory support for intractable heart failure as a bridge to transplantation has been used infrequently in children. The lack of clinically available ventricular assist devices has resulted in the use of conventional extracorporeal circuits with oxygenator as the main modality for circulatory support. In this study we reviewed our experience with extracorporeal membrane oxygenation (ECMO) support in children with irreversible heart failure who were awaiting heart transplantation.Since 1985, 14 children were placed on ECMO support for circulatory failure and were considered candidates for heart transplantation: 8 children had postcardiotomy contractile failure, 3 had dilated cardiomyopathy, and 3 had viral myocarditis. Five of these children had cardiac arrest and were placed on support during cardiopulmonary resuscitation. Mean duration of ECMO support was 109 +/- 20 hours. Eight patients developed pulmonary edema requiring decompression of the left ventricle, 3 by blade atrial septostomy and 5 by left atrial vent cannula. Nine of 14 received a heart transplant, 1 child recovered spontaneously (myocarditis), and 4 died of sepsis on ECMO. Of the children who received transplants, 6 were early survivors with 1 late death (lymphoproliferative disease), for a total of 7 of 14 (50%) early and 6 of 14 (43%) late survivors.Our experience suggests that ECMO is an effective means of circulatory support as a bridge to transplantation in children. Decompression of the left ventricle is often required to prevent pulmonary edema. Sepsis and bleeding remain a limitation to prolonged mechanical support with ECMO in children.

The Ag-staining technique was employed to investigate the activity of the nucleolar organizer during spermatogenesis of the isopod crustacean Asellus aquaticus. The most interesting results of this investigation were: (1) The NORs remain continuously Ag-stained for the whole of spermatogenesis until maturation of the sperm, contrary to the situation in the other species so far described; (2) In the gonial mitotic cells the NORs of a single pair, in the meiotic cells of both pairs of chromosomes that have the NORs, are Ag-stained and therefore active; (3) Some of the individuals examined exhibited additional NORs.

SUMMARYIn the present work we study the structure of the Ag-positive chromosome core in normally condensed and DAPI-undercondensed human chromosomes. In the chromosomes from untreated cultures the core shows no discontinuities all along the chromosome length except for the paracentromeric heterochromatic area of chromosome 9. The undercondensed areas of DAPI-treated chromosomes display alterations in their silver affinity which varies with the area from heavy precipitation of silver grains to the absence of staining.

A silver-stainable chromatid core is visualized under the light microscope on human leukocyte chromosomes by treating fixed chromosomes with 2M NaCl. An aminoacid which is not part of histone composition, 3H-tryptophan, is used to label the synthesis and location of non-histone proteins and to study the effect on these proteins of treatment with 2M NaCl and 0.2N HCl to visualize the core. 2M NaCl is shown to remove from nuclei and chromosomes an appreciable fraction of acid proteins, as well as all those synthesized during the two hours preceding the metaphase. 3H-Try labelling seems to preferentially affect only one chromatid per chromosome. The silver-stainable halocs appearing around numerous nuclei after treatment with 2M NaCl and 0.2N HCl are found to be labelled by 3H-Try and not by 3H-TdR.

In a previous paper it was shown that the AT-specific DNA ligand DAPI, when supplied in culture, induces specific regions lacking spiralization on human chromosomes. In the present investigation the action of DAPI as related to the cell cycle was investigated in three different ways: (1) treatment of cultures with DAPI for different periods of time; (2) simultaneous treatment of cultures with DAPI and [ 3 H]thymidine; (3) determination of penetration rate of DAPI in cultured cells. Taken as a whole, our data show that the drug can act as an undercondensing agent also when supplied to the cells after DNA synthesis and that its cell penetration is slow and increases with time.