In this phase I study (BLOOM), osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was evaluated in patients with leptomeningeal metastases (LMs) ...from EGFR-mutated (EGFRm) advanced non-small-cell lung cancer (NSCLC) whose disease had progressed on previous EGFR-TKI therapy.
Patients with cytologically confirmed LM received osimertinib 160 mg once daily. Objectives were to assess confirmed objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and safety. Additional efficacy evaluations included changes from baseline in CSF cytology and neurologic examination. Measurable lesions were assessed by investigator according to RECIST version 1.1. LMs were assessed by neuroradiologic blinded central independent review (BICR) according to Response Assessment in Neuro-Oncology LM radiologic criteria and by investigator.
Forty-one patients were enrolled. LM ORR and DoR by neuroradiologic BICR were 62% (95% CI, 45% to 78%) and 15.2 months (95% CI, 7.5 to 17.5 months), respectively. Overall, ORR by investigator was 41% (95% CI, 26% to 58%), and median DoR was 8.3 months (95% CI, 5.6 to 16.5 months). Median investigator-assessed PFS was 8.6 months (95% CI, 5.4 to 13.7 months) with 78% maturity; median OS was 11.0 months (95% CI, 8.0 to 18.0 months) with 68% maturity. CSF tumor cell clearance was confirmed in 11 (28%; 95% CI, 15% to 44%) of 40 patients. Neurologic function was improved in 12 (57%) of 21 patients with an abnormal assessment at baseline. The adverse event and PK profiles were consistent with previous reports for osimertinib.
Osimertinib showed meaningful therapeutic efficacy in the CNS and a manageable safety profile at 160 mg once daily in patients with EGFRm NSCLC and LM.
Mutations in the
(
) gene were among the first genetic alterations implicated in meningioma tumorigenesis, based on analysis of neurofibromatosis type 2 (NF2) patients who not only develop vestibular ...schwannomas but later have a high incidence of meningiomas. The
gene product, merlin, is a tumor suppressor that is thought to link the actin cytoskeleton with plasma membrane proteins and mediate contact-dependent inhibition of proliferation. However, the early recognition of the crucial role of
mutations in the pathogenesis of the majority of meningiomas has not yet translated into useful clinical insights, due to the complexity of merlin's many interacting partners and signaling pathways. Next-generation sequencing studies and increasingly sophisticated
-deletion-based
and
models have helped elucidate the consequences of merlin loss in meningioma pathogenesis. In this review, we seek to summarize recent findings and provide future directions toward potential therapeutics for this tumor.
Since the first U.S. Food and Drug Administration approval in 2011, over 50,000 patients have undergone TAVR in the United States alone. Echocardiographic assessment of AS severity has been performed ...before making the decision that AVR is needed. ...echocardiography is not discussed in detail in this document; readers are referred to recent review papers on this topic for additional information.
Background
Soft tissue allografts are essential for revision and multiple ligament surgeries in the knee, where donor-site morbidity is an issue. However, the use of allografts is associated with a ...higher failure rate of osteointegration. Mesenchymal stem cells (MSCs) are investigated as potential agents to enhance bone tunnel and tendon healing.
Purpose
This study was conducted to analyze the effect of coating allografts with MSCs on the quality and rate of osteointegration at the allograft tendon and bone interface, and the biomechanical properties of these enhanced anterior cruciate ligament (ACL) grafts compared with controls.
Study Design
Descriptive laboratory study.
Methods
Bilateral ACL reconstructions using Achilles tendon allografts were performed in 36 rabbits. On 1 limb, the graft was coated with autogenous MSCs in a fibrin glue carrier, while the contralateral limb served as a control with no MSCs. The reconstructions were assessed histologically and biomechanically at 2, 4, and 8 weeks.
Results
At 8 weeks, histologic analysis of the controls revealed the development of mature scar tissue resembling Sharpey fibers spanning the tendon-bone interface. In contrast, the MSC-enhanced reconstructions showed a mature zone of fibrocartilage blending from bone to the allograft, strongly resembling a normal ACL insertion. On biomechanical testing, the MSC-enhanced grafts had significantly higher load-to-failure rates than controls. However, the stiffness and Young's modulus were lower in the treatment group.
Conclusions
The application of MSCs at the allograft tendon-bone interface during ACL reconstruction results in the development of an intervening zone of fibrocartilage. The use of MSCs to enhance allograft osteointegration is a novel method offering the potential of more physiologic and earlier healing, although further investigation must be conducted to improve the biomechanical strength.
Clinical Relevance
Mesenchymal stem cells can improve the biologic properties of soft tissue allograft healing. Combined with the decrease in donor-site morbidity, allografts are a viable choice for the sports medicine surgeon.
This work demonstrates the high-frequency and high-power performance capacity of GaN high electron mobility transistors (HEMTs) on Si substrates. Using a T-gate and n++-GaN source/drain contacts, the ...InAlN/GaN HEMT with a gate length of 55 nm and a source-drain spacing of 175 nm shows a maximum drain current ID,MAX of 2.8 A/mm and a peak transconductance gm of 0.66 S/mm. The same HEMT exhibits a forward-current-gain cutoff frequency fT of 250 GHz and a maximum frequency of oscillation fMAX of 204 GHz. The ID,MAX, peak gm and fT-fMAX product are among the best reported for GaN HEMTs on Si, which are very close to the state-of-the-art depletion-mode GaN HEMTs on SiC without a back barrier. Given the low cost of Si and the high compatibility with CMOS circuits, GaN HEMTs on Si prove to be particularly attractive for cost-sensitive applications.
We have previously described a prognostic transcriptional signature in CD8 T cells that separates patients with IBD into two phenotypically distinct subgroups, termed IBD1 and IBD2. Here we sought to ...develop a blood-based test that could identify these subgroups without cell separation, and thus be suitable for clinical use in Crohn's disease (CD) and ulcerative colitis (UC).
Patients with active IBD were recruited before treatment. Transcriptomic analyses were performed on purified CD8 T cells and/or whole blood. Phenotype data were collected prospectively. IBD1/IBD2 patient subgroups were identified by consensus clustering of CD8 T cell transcriptomes. In a training cohort, machine learning was used to identify groups of genes ('classifiers') whose differential expression in whole blood recreated the IBD1/IBD2 subgroups. Genes from the best classifiers were quantitative (q)PCR optimised, and further machine learning was used to identify the optimal qPCR classifier, which was locked down for further testing. Independent validation was sought in separate cohorts of patients with CD (n=66) and UC (n=57).
In both validation cohorts, a 17-gene qPCR-based classifier stratified patients into two distinct subgroups. Irrespective of the underlying diagnosis, IBDhi patients (analogous to the poor prognosis IBD1 subgroup) experienced significantly more aggressive disease than IBDlo patients (analogous to IBD2), with earlier need for treatment escalation (hazard ratio=2.65 (CD), 3.12 (UC)) and more escalations over time (for multiple escalations within 18 months: sensitivity=72.7% (CD), 100% (UC); negative predictive value=90.9% (CD), 100% (UC)).
This is the first validated prognostic biomarker that can predict prognosis in newly diagnosed patients with IBD and represents a step towards personalised therapy.
Detailed population-level description of the human immune system has recently become achievable. We used a 'systems-level' approach to establish a resource of cellular immune profiles of 670 healthy ...individuals. We report a high level of interindividual variation, with low longitudinal variation, at the level of cellular subset composition of the immune system. Despite the profound effects of antigen exposure on individual antigen-specific clones, the cellular subset structure proved highly elastic, with transient vaccination-induced changes followed by a return to the individual's unique baseline. Notably, the largest influence on immunological variation identified was cohabitation, with 50% less immunological variation between individuals who share an environment (as parents) than between people in the wider population. These results identify local environmental conditions as a key factor in shaping the human immune system.
It is generally assumed that protein clients fold following their release from chaperones instead of folding while remaining chaperone-bound, in part because binding is assumed to constrain the ...mobility of bound clients. Previously, we made the surprising observation that the ATP-independent chaperone Spy allows its client protein Im7 to fold into the native state while continuously bound to the chaperone. Spy apparently permits sufficient client mobility to allow folding to occur while chaperone bound. Here, we show that strengthening the interaction between Spy and a recently discovered client SH3 strongly inhibits the ability of the client to fold while chaperone bound. The more tightly Spy binds to its client, the more it slows the folding rate of the bound client. Efficient chaperone-mediated folding while bound appears to represent an evolutionary balance between interactions of sufficient strength to mediate folding and interactions that are too tight, which tend to inhibit folding.
The interferon-inducible transmembrane (IFITM) protein family represents a new class of cellular restriction factors that block early stages of viral replication; the underlying mechanism is ...currently not known. Here we provide evidence that IFITM proteins restrict membrane fusion induced by representatives of all three classes of viral membrane fusion proteins. IFITM1 profoundly suppressed syncytia formation and cell-cell fusion induced by almost all viral fusion proteins examined; IFITM2 and IFITM3 also strongly inhibited their fusion, with efficiency somewhat dependent on cell types. Furthermore, treatment of cells with IFN also markedly inhibited viral membrane fusion and entry. By using the Jaagsiekte sheep retrovirus envelope and influenza A virus hemagglutinin as models for study, we showed that IFITM-mediated restriction on membrane fusion is not at the steps of receptor- and/or low pH-mediated triggering; instead, the creation of hemifusion was essentially blocked by IFITMs. Chlorpromazine (CPZ), a chemical known to promote the transition from hemifusion to full fusion, was unable to rescue the IFITM-mediated restriction on fusion. In contrast, oleic acid (OA), a lipid analog that generates negative spontaneous curvature and thereby promotes hemifusion, virtually overcame the restriction. To explore the possible effect of IFITM proteins on membrane molecular order and fluidity, we performed fluorescence labeling with Laurdan, in conjunction with two-photon laser scanning and fluorescence-lifetime imaging microscopy (FLIM). We observed that the generalized polarizations (GPs) and fluorescence lifetimes of cell membranes expressing IFITM proteins were greatly enhanced, indicating higher molecularly ordered and less fluidized membranes. Collectively, our data demonstrated that IFITM proteins suppress viral membrane fusion before the creation of hemifusion, and suggested that they may do so by reducing membrane fluidity and conferring a positive spontaneous curvature in the outer leaflets of cell membranes. Our study provides novel insight into the understanding of how IFITM protein family restricts viral membrane fusion and infection.
The folding of proteins into their native structure is crucial for the functioning of all biological processes. Molecular chaperones are guardians of the proteome that assist in protein folding and ...prevent the accumulation of aberrant protein conformations that can lead to proteotoxicity. ATP-independent chaperones do not require ATP to regulate their functional cycle. Although these chaperones have been traditionally regarded as passive holdases that merely prevent aggregation, recent work has shown that they can directly affect the folding energy landscape by tuning their affinity to various folding states of the client. This review focuses on emerging paradigms in the mechanism of action of ATP-independent chaperones and on the various modes of regulating client binding and release.
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