Peripheral blood MФ–cancer cell fusion hybrids identified in cancer patients correlate with disease stage and overall survival.

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AbstreetThispaper proposes a set of efficient primitives for process synchronization in muitiprocessors. The only assumptions made in developing the set of primitives are that hardware combining is not implemented in the hterconnect, and (in one case) that the interconnect supports broadcast.The primitives make use of synchronization bits (syncbits) to provide a simple mechanism for mutual exclusion. The proposed implementation of the primitives includes efEcient (Le. kxal) busy-waiting for syncbit& In addition, a hardware-supported mechanism for maintaining a first-come ih-st-serve queue of requests for a syncbit is proposed. This queueing mechanism aiiows for a very efEcient implementation of, as well as fair access to, binary semaphores.We also Propose t0 implement Fetch-and-Add with combining in software rather than hardware. This allows an architecture to scale to a huge number of processors while avoiding the cost of hardware combining.Scenarios for common synchronization events such as work queues and barriers are presented to demonstrate the generality and ease of use of the proposed primitives. The efficient implementation of the primitives is simpler if the multiprocessor has a hardware cache-consistency protocol. To illustrate this point, we outline how the primitives would be implemented in the Multicube multiprocessor [GoWofB].

SARS-CoV-2 and its variants continue to infect hundreds of thousands every day despite the rollout of effective vaccines. Therefore, it is essential to understand the levels of protection that these vaccines provide in the face of emerging variants. Here, we report two demographically balanced cohorts of BNT162b2 vaccine recipients and COVID-19 patients, from which we evaluate neutralizing antibody titers against SARS-CoV-2 as well as the B.1.1.7 (alpha) and B.1.351 (beta) variants. We show that both B.1.1.7 and B.1.351 are less well neutralized by serum from vaccinated individuals, and that B.1.351, but not B.1.1.7, is less well neutralized by convalescent serum. We also find that the levels of variant-specific anti-spike antibodies are proportional to neutralizing activities. Together, our results demonstrate the escape of the emerging SARS-CoV-2 variants from neutralization by serum antibodies, which may lead to reduced protection from re-infection or increased risk of vaccine breakthrough.

Oncogenic ROS1 fusion proteins are molecular drivers in multiple malignancies, including a subset of non-small cell lung cancer (NSCLC). The phylogenetic proximity of the ROS1 and anaplastic lymphoma kinase (ALK) catalytic domains led to the clinical repurposing of the Food and Drug Administration (FDA)-approved ALK inhibitor crizotinib as a ROS1 inhibitor. Despite the antitumor activity of crizotinib observed in both ROS1-and ALK-rearranged NSCLC patients, resistance due to acquisition of ROS1 or ALK kinase domain mutations has been observed clinically, spurring the development of second-generation inhibitors. Here, we profile the sensitivity and selectivity of seven ROS1 and/or ALK inhibitors at various levels of clinical development. In contrast to crizotinib's dual ROS1/ALK activity, cabozantinib (XL-184) and its structural analog foretinib (XL-880) demonstrate a striking selectivity for ROS1 over ALK. Molecular dynamics simulation studies reveal structural features that distinguish the ROS1 and ALK kinase domains and contribute to differences in binding site and kinase selectivity of the inhibitors tested. Cell-based resistance profiling studies demonstrate that the ROS1-selective inhibitors retain efficacy against the recently reported CD74-ROS1 G2032R mutant whereas the dual ROS1/ALK inhibitors are ineffective. Taken together, inhibitor profiling and stringent characterization of the structure-function differences between the ROS1 and ALK kinase domains will facilitate future rational drug design for ROS1-and ALK-driven NSCLC and other malignancies.onstitutively activated kinase fusion proteins that arise from somatic chromosomal rearrangements are frequent drivers of malignant transformation in cancer and represent a targetable vulnerability for clinical intervention. The clinical success of the tyrosine kinase inhibitor (TKI) imatinib in targeting the oncogenic BCR-ABL1 fusion protein in chronic myeloid leukemia (CML) motivated efforts to identify and target oncogenic kinases in other cancers (1-3). One such setting is non-small cell lung cancer (NSCLC), where chromosomal rearrangements of the receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) are found in 4-5% of patients (4, 5). The validation of rearranged ALK as an oncogenic driver prompted the discovery and clinical implementation of crizotinib as the first clinical targeted inhibitor for use in ALK fusionpositive NSCLC (6, 7).Fusion proteins involving the highly related kinase ROS1, an orphan RTK of the insulin receptor family, are present in ∼1% of NSCLC patients. ROS1 rearrangements span a variety of fusion partners across several other epithelial malignancies, including cholangiocarcinoma, gastric cancer, and ovarian cancer (4, 8). CD74-ROS1 is the most frequent ROS1 fusion detected in NSCLC. ROS1 fusion proteins are transforming drivers that contribute to tumorigenesis or tumor progression in multiple experimental model systems (9)(10)(11).Approximately 75,000 and 15,000 new NSCLC patients per year are anticipated to harbor tumors...