Amifostine (WR-2721) shortens the engraftment period of 4-hydroperoxycyclophosphamide-purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support

4-Hydroperoxycyclophosphamide (4-HC), a commonly used marrow-purging agent, is active against many tumors, but is also toxic to normal marrow progenitors. Amifostine (WR-2721) is a sulfhydryl compound with chemoprotectant activity. Preclinical studies using suspensions of bone marrow and breast cancer cells demonstrated that ex vivo treatment with amifostine followed by 4-HC resulted in protection of marrow progenitors, with no compromise in the antitumor effect of 4-HC. This fact stimulated the development of a clinical trial. Bone marrow was harvested from 15 poor-prognosis breast cancer patients and randomly assigned to ex vivo treatment with amifostine followed by 4-HC (amifostine + 4-HC), or treatment with 4-HC alone. High-dose chemotherapy was then administered followed by infusion of the purged autologous bone marrow support (ABMS). Leukocyte engraftment, defined as a white blood cell count > or = 1 x 10(9)/L, was achieved in an average of 26 days for patients whose marrow was purged with amifostine + 4-HC versus 36 days for patients whose marrow was purged with 4-HC alone (P = .032). The average number of platelet transfusions (12 v 29; P = .017) and days of antibiotic therapy (28 v 40; P = .012) were significantly less for patients whose marrow was exposed to amifostine + 4-HC, compared with 4-HC alone. Unpurged backup marrow fractions were infused into three patients whose marrow was purged with 4-HC alone, because of inadequate marrow recovery. None of the patients who received amifostine + 4-HC-purged marrow required a backup marrow fraction. Complete remissions were achieved in 83% of patients with measurable disease, with no difference between the two cohorts. Forty-three percent of patients remained alive and progression-free at a mean of 13 months posttransplant. There was no significant difference in the rate or pattern of relapse for patients whose marrow was purged with amifostine + 4-HC compared with those whose marrow was purged with 4-HC alone. Ex vivo treatment of marrow with amifostine significantly shortens the time to marrow recovery, thereby reducing the risk of myelosuppressive complications in breast cancer patients receiving high-dose chemotherapy and 4-HC-purged ABMS. Since supportive care requirements are also significantly decreased, amifostine may reduce the cost of such therapy.     

强调材料——清华大学核能技术研究院花园的再设计

1设计意识核能研究院花园再设计的项目证明了朱育帆在本设计中的一个偏好的原发点:材料意识和对材料精确性的把握。从这种材料意识出发,他的设计赋予了这个地点一种新的愉悦氛围,甚至是对当代中国风景园林境遇的一种注释。     

Digital repository: preservation environment and policy implementation

Distributed digital repositories can be used to address critical issues of long-term digital preservation and disaster management for large data centers. A policy-driven system provides an ideal solution for managing distributed repositories that require high flexibility and high configurability. Recent studies demonstrate that the integrated Rule-Oriented Data System, a peer-to-peer server middleware, provides the requisite dynamic extensibility needed to manage time-varying policies, automate validation of assessment criteria, manage ingestion processes, manage access policies, and manage preservation policies. The policy management can be implemented underneath existing digital library infrastructure such as Fedora.     

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel K_v1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.     

ON THE ROBUST PREDICTION AND INTERPOLATION OF TIME SERIES IN THE PRESENCE OF CORRELATED NOISE

Abstract. We consider the problem of predicting and interpolating linearly a time series which can be represented as the sum of a model process with known spectral density and a noise process. The spectral density of the noise process is unknown with the exception of an upper bound for its integral. Some partial information of quite general kind about the cross spectral density of model and noise is available. We prove the existence of a robust predictor which minimizes the maximal mean-square error, where the maximum is taken over all spectral densities which may arise from the circumstances described above as spectral density of the predicted time series. An analogous result holds for the related interpolation problem. We describe how to derive the minimax robust predictor and interpolator in concrete situations. The method is illustrated by determining the robust predictor explicitly for three examples where model and noise may be arbitrarily, only causally or not at all correlated.     

Universities in Evolutionary Systems of Innovation

This paper criticizes the current narrow view on the role of universities in knowledge‐based economies. We propose to extend the current policy framework of universities in national innovation systems (NIS) to a more dynamic one, based on evolutionary economic principles. The main reason is that this dynamic view fits better with the practice of innovation processes. We contribute on ontological and methodological levels to the literature and policy discussions on the effectiveness of university‐industry knowledge transfer and the third mission of universities. We conclude with a discussion of the policy implications for the main stakeholders.     

Investigations of the copper isotope effect in oxygen-deficient YBa2Cu3O7−δ

We present data on the copper isotope effect (⁶³Cu-⁶⁵Cu), C_u =-nT_c/nm_Cu, for two isotopic pairs of oxygen-deficient YBa₂Cu₃O_7–, where varies between 0.06 and 0.52. _Cu is below 0.01 at =0.06 (fully oxygenated), it takes values between –0.14 and –0.34 in the 60 K plateau. Larger negative values of _Cu are observed away from the plateau. The dependence of _Cu is similar to that of the pressure effect dnT_c/dP.     

The primary aortoenteric fistula in The Netherlands--the unpublished cases

OBJECTIVE: Primary aortoenteric fistula is a rare disorder of which only four patients have been reported in the Dutch literature so far. The objective of our study was to obtain more realistic figures on the incidence of this condition, with data on the clinical presentation, diagnostic procedures, treatment and results in a group of patients not previously reported as "case histories". METHODS: A questionnaire was sent to all surgical clinics in The Netherlands. Out of 180 questionnaires, 102 have been returned reporting 27 patients to which data of eight others treated in our own institution were added. RESULTS: In all but one of these 29 patients the fistula was caused by an atherosclerotic aneurysm, the one exception being caused by an ingested cocktail pin. Gastrointestinal haemorrhage was the predominant symptom, being present in 28 of the patients, while the complete triad of haemorrhage, pain and a pulsating mass was found in only eight patients. Twenty-seven patients were treated with an in situ graft of which 14 are doing well at long term follow-up. CONCLUSIONS: Primary aortoenteric fistula is far more common than one would expect from the number of patients reported in literature. A high index of suspicion based on a complete physical examination remains the key to a correct diagnosis. Direct closure of the intestine and in situ grafting of the aorta is the treatment of first choice.