Type Inference for Deadlock Detection in a Multithreaded Polymorphic Typed Assembly Language

We previously developed a polymorphic type system and a type checker for a multithreaded lock-based polymorphic typed assembly language (MIL) that ensures that well-typed programs do not encounter race conditions. This paper extends such work by taking into consideration deadlocks. The extended type system verifies that locks are acquired in the proper order. Towards this end we require a language with annotations that specify the locking order. Rather than asking the programmer (or the compiler's backend) to specifically annotate each newly introduced lock, we present an algorithm to infer the annotations. The result is a type checker whose input language is non-decorated as before, but that further checks that programs are exempt from deadlocks

Clinical Laboratory Testing Practices in Diffuse Gliomas Prior to Publication of 2021 World Health Organization Classification of Central Nervous System Tumors

CONTEXT.—: Integration of molecular data into glioma classification supports diagnostic, prognostic, and therapeutic decision-making; however, testing practices for these informative biomarkers in clinical laboratories remain unclear. OBJECTIVE.—: To examine the prevalence of molecular testing for clinically relevant biomarkers in adult and pediatric gliomas through review of a College of American Pathologists proficiency testing survey prior to the release of the 2021 World Health Organization Classification of Central Nervous System Tumors. DESIGN.—: College of American Pathologists proficiency testing 2020 survey results from 96 laboratories performing molecular testing for diffuse gliomas were used to determine the use of testing for molecular biomarkers in gliomas. RESULTS.—: The data provide perspective into the testing practices for diffuse gliomas from a broad group of clinical laboratories in 2020. More than 98% of participating laboratories perform testing for glioma biomarkers recognized as diagnostic for specific subtypes, including IDH. More than 60% of laboratories also use molecular markers to differentiate between astrocytic and oligodendroglial lineage tumors, with some laboratories providing more comprehensive analyses, including prognostic biomarkers, such as CDKN2A/B homozygous deletions. Almost all laboratories test for MGMT promoter methylation to identify patients with an increased likelihood of responding to temozolomide. CONCLUSIONS.—: These findings highlight the state of molecular testing in 2020 for the diagnosis and classification of diffuse gliomas at large academic medical centers. The findings show that comprehensive molecular testing is not universal across clinical laboratories and highlight the gaps between laboratory practices in 2020 and the recommendations in the 2021 World Health Organization Classification of Central Nervous System Tumors

Efficacy of an integrative approach for bipolar disorder: preliminary results from a randomized controlled trial

Background. Bipolar Disorder (BD) represents one of the most therapeutically complex psychiatric disorders. The development of a feasible comprehensive psychological approach to complement pharmacotherapy to improve its clinical management is required. The main objective of the present randomized controlled trial (RCT) was to test the efficacy of a novel adjunctive treatment entitled integrative approach in patients with BD, including: psychoeducation, mindfulness training, and functional remediation. Methods. This is a parallel two-armed, rater-blind RCT of an integrative approach plus treatment as usual (TAU), versus TAU alone. Participants were recruited at the Hospital Clinic of Barcelona and randomized to one of the two conditions. They were assessed at baseline and after finishing the intervention. The main outcome variable included changes in psychosocial functioning assessed through the Functioning Assessment Short Test (FAST). Results. After finishing the treatment, the repeated-measures analyses revealed a significant group x time interaction in favor of the patients who received the integrative approach (n=28) compared to the TAU group (n=37) (Pillai’s trace= .10; F(1,57)=6.9 p=.01), improving the functional outcome. Significant effects were also found in two out of the six domains of the FAST, including the cognitive domain (Pillai’s trace=.25; F(1,57)=19.1; p<.001) and leisure time (Pillai’s trace=.11; F(1,57)=7.15; p=.01). Regarding the secondary outcomes, a significant group x time interaction in Hamilton Depression Rating Scale changes was detected (Pillai’s trace= .08; F(1,62)=5.6; p=.02). Conclusion. This preliminary study suggest that the Integrative Approach represents a promising cost-effective therapy to improve psychosocial functioning and residual depressive symptoms in patients suffering from BD. </p

A foundation for runtime monitoring

Runtime Verification is a lightweight technique that complements other verification methods in an effort to ensure software correctness. The technique poses novel questions to software engineers: it is not easy to identify which specifications are amenable to runtime monitor-ing, nor is it clear which monitors effect the required runtime analysis correctly. This exposition targets a foundational understanding of these questions. Particularly, it considers an expressive specification logic (a syntactic variant of the modal μ-calculus) that is agnostic of the verification method used, together with an elemental framework providing an operational semantics for the runtime analysis performed by monitors. The correspondence between the property satisfactions in the logic on the one hand, and the verdicts reached by the monitors performing the analysis on the other, is a central theme of the study. Such a correspondence underpins the concept of monitorability, used to identify the subsets of the logic that can be adequately monitored for by RV. Another theme of the study is that of understanding what should be expected of a monitor in order for the verification process to be correct. We show how the monitor framework considered can constitute a basis whereby various notions of monitor correctness may be defined and investigated.peer-reviewe

Molecular Analysis of Precursor Lesions in Familial Pancreatic Cancer

PMCID: PMC3553106This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

A Foundation for Runtime Monitoring

Runtime Verification is a lightweight technique that complements other verification methods in an effort to ensure software correctness. The technique poses novel questions to software engineers: it is not easy to identify which specifications are amenable to runtime monitoring, nor is it clear which monitors effect the required runtime analysis correctly. This exposition targets a foundational understanding of these questions. Particularly, it considers an expressive specification logic (a syntactic variant of the mmucalc) that is agnostic of the verification method used, together with an elemental framework providing an operational semantics for the runtime analysis performed by monitors. The correspondence between the property satisfactions in the logic on the one hand, and the verdicts reached by the monitors performing the analysis on the other, is a central theme of the study. Such a correspondence underpins the concept of monitorability, used to identify the subsets of the logic that can be adequately monitored for by RV. Another theme of the study is that of understanding what should be expected of a monitor in order for the verification process to be correct. We show how the monitor framework considered can constitute a basis whereby various notions of monitor correctness may be defined and investigated

A highly invasive human glioblastoma pre-clinical model for testing therapeutics

Animal models greatly facilitate understanding of cancer and importantly, serve pre-clinically for evaluating potential anti-cancer therapies. We developed an invasive orthotopic human glioblastoma multiforme (GBM) mouse model that enables real-time tumor ultrasound imaging and pre-clinical evaluation of anti-neoplastic drugs such as 17-(allylamino)-17-demethoxy geldanamycin (17AAG). Clinically, GBM metastasis rarely happen, but unexpectedly most human GBM tumor cell lines intrinsically possess metastatic potential. We used an experimental lung metastasis assay (ELM) to enrich for metastatic cells and three of four commonly used GBM lines were highly metastatic after repeated ELM selection (M2). These GBM-M2 lines grew more aggressively orthotopically and all showed dramatic multifold increases in IL6, IL8, MCP-1 and GM-CSF expression, cytokines and factors that are associated with GBM and poor prognosis. DBM2 cells, which were derived from the DBTRG-05MG cell line were used to test the efficacy of 17AAG for treatment of intracranial tumors. The DMB2 orthotopic xenografts form highly invasive tumors with areas of central necrosis, vascular hyperplasia and intracranial dissemination. In addition, the orthotopic tumors caused osteolysis and the skull opening correlated to the tumor size, permitting the use of real-time ultrasound imaging to evaluate antitumor drug activity. We show that 17AAG significantly inhibits DBM2 tumor growth with significant drug responses in subcutaneous, lung and orthotopic tumor locations. This model has multiple unique features for investigating the pathobiology of intracranial tumor growth and for monitoring systemic and intracranial responses to antitumor agents

Purine metabolism regulates DNA repair and therapy resistance in glioblastoma

Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming therapy resistance. Treatments that are effective independent of genotype are urgently needed. By correlating intracellular metabolite levels with radiation resistance across dozens of genomically-distinct models of GBM, we find that purine metabolites, especially guanylates, strongly correlate with radiation resistance. Inhibiting GTP synthesis radiosensitizes GBM cells and patient-derived neurospheres by impairing DNA repair. Likewise, administration of exogenous purine nucleosides protects sensitive GBM models from radiation by promoting DNA repair. Neither modulating pyrimidine metabolism nor purine salvage has similar effects. An FDA-approved inhibitor of GTP synthesis potentiates the effects of radiation in flank and orthotopic patient-derived xenograft models of GBM. High expression of the rate-limiting enzyme of de novo GTP synthesis is associated with shorter survival in GBM patients. These findings indicate that inhibiting purine synthesis may be a promising strategy to overcome therapy resistance in this genomically heterogeneous disease

Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system

Primary melanocytic neoplasms of the central nervous system (CNS) are uncommon neoplasms derived from melanocytes that normally can be found in the leptomeninges. They cover a spectrum of malignancy grades ranging from low-grade melanocytomas to lesions of intermediate malignancy and overtly malignant melanomas. Characteristic genetic alterations in this group of neoplasms have not yet been identified. Using direct sequencing, we investigated 19 primary melanocytic lesions of the CNS (12 melanocytomas, 3 intermediate-grade melanocytomas, and 4 melanomas) for hotspot oncogenic mutations commonly found in melanocytic tumors of the skin (BRAF, NRAS, and HRAS genes) and uvea (GNAQ gene). Somatic mutations in the GNAQ gene at codon 209, resulting in constitutive activation of GNAQ, were detected in 7/19 (37%) tumors, including 6/12 melanocytomas, 0/3 intermediate-grade melanocytomas, and 1/4 melanomas. These GNAQ-mutated tumors were predominantly located around the spinal cord (6/7). One melanoma carried a BRAF point mutation that is frequently found in cutaneous melanomas (c.1799 T>A, p.V600E), raising the question whether this is a metastatic rather than a primary tumor. No HRAS or NRAS mutations were detected. We conclude that somatic mutations in the GNAQ gene at codon 209 are a frequent event in primary melanocytic neoplasms of the CNS. This finding provides new insight in the pathogenesis of these lesions and suggests that GNAQ-dependent mitogen-activated kinase signaling is a promising therapeutic target in these tumors. The prognostic and predictive value of GNAQ mutations in primary melanocytic lesions of the CNS needs to be determined in future studies