Residual Stresses in Surgical Growing Rods.

The treatment of early onset scoliosis using surgical growing rods suffers from high failure rate. Fatigue resistance can be improved by inducing compressive residual stresses within the near surface region. An in-depth investigation of the residual stresses profile evolution is performed through the sequence of material processing steps followed by surgeons handling operations, in connection to material properties. The final goal is to guide further improvements of growing rod lifetime. Residual stress evaluation was carried out on Ti-6Al-4V rods using digital image correlation applied to microbeam ring-core milling by focused ion beam. This provided experimental stress profiles in shot-peened rods before and after bending and demonstrated that compressive residual stresses are maintained at both concave and convex rod sides. A finite element model using different core and skin conditions was validated by comparison to experiments. The combination of an initial shot peening profile associated with a significant level of backstress was found to primarily control the generation of compressive stresses at the rod surface after bending. Guidelines to promote larger compressive stresses at the surface were formulated based on a parametric analysis. The analysis revealed the first order impact of the initial yield strength, kinematic hardening parameters and intensity of the shot peening operation, while the bending angle and the depth of shot peening stresses were found to be of minor importance. Materials exhibiting large kinematic hardening and low yield strength should be selected in order to induce compressive residual stresses at key fatigue initiation site.

Complex intracranial aneurysms: a DELPHI study to define associated characteristics.

PURPOSE: Intracranial aneurysms present significant health risks, as their rupture leads to subarachnoid haemorrhage, which in turn has high morbidity and mortality rates. There are several elements affecting the complexity of an intracranial aneurysm. However, criteria for defining a complex intracranial aneurysm (CIA) in open surgery and endovascular treatment could differ, and actually there is no consensus on the definition of a "complex" aneurysm. This DELPHI study aims to assess consensus on variables defining a CIA. METHODS: An international panel of 50 members, representing various specialties, was recruited to define CIAs through a three-round Delphi process. The panelists participated in surveys with Likert scale responses and open-ended questions. Consensus criteria were established to determine CIA variables, and statistical analysis evaluated consensus and stability. RESULTS: In open surgery, CIAs were defined by fusiform or blister-like shape, dissecting aetiology, giant size (≥ 25 mm), broad neck encasing parent arteries, extensive neck surface, wall calcification, intraluminal thrombus, collateral branch from the sac, location (AICA, SCA, basilar), vasospasm context, and planned bypass (EC-IC or IC-IC). For endovascular treatment, CIAs included giant size, very wide neck (dome/neck ratio ≤ 1:1), and collateral branch from the sac. CONCLUSIONS: The definition of aneurysm complexity varies by treatment modality. Since elements related to complexity differ between open surgery and endovascular treatment, these consensus criteria of CIAs could even guide in selecting the best treatment approach.

The efficacy of cariprazine on cognition: a post hoc analysis from phase II/III clinical trials in bipolar mania, bipolar depression, and schizophrenia.

OBJECTIVE: To investigate the effect of cariprazine on cognitive symptom change across bipolar I disorder and schizophrenia. METHODS: Post hoc analyses of 3- to 8-week pivotal studies in bipolar I depression and mania were conducted; one schizophrenia trial including the Cognitive Drug Research System attention battery was also analyzed. Outcomes of interest: Montgomery-Åsberg Depression Rating Scale [MADRS], Functioning Assessment Short Test [FAST], Positive and Negative Syndrome Scale [PANSS]). LSMDs in change from baseline to end of study were reported in the overall intent-to-treat population and in patient subsets with specified levels of baseline cognitive symptoms or performance. RESULTS: In patients with bipolar depression and at least mild cognitive symptoms, LSMDs were statistically significant for cariprazine vs placebo on MADRS item 6 (3 studies; 1.5 mg=-0.5 [P<.001]; 3 mg/d=-0.2 [P<.05]) and on the FAST Cognitive subscale (1 study; 1.5 mg/d=-1.4; P=.0039). In patients with bipolar mania and at least mild cognitive symptoms, the LSMD in PANSS Cognitive subscale score was statistically significant for cariprazine vs placebo (3 studies; -2.1; P=.001). In patients with schizophrenia and high cognitive impairment, improvement in power of attention was observed for cariprazine 3 mg/d vs placebo (P=.0080), but not for cariprazine 6 mg/d; improvement in continuity of attention was observed for cariprazine 3 mg/d (P=.0012) and 6 mg/d (P=.0073). CONCLUSION: These post hoc analyses provide preliminary evidence of greater improvements for cariprazine vs placebo across cognitive measures in patients with bipolar I depression and mania, and schizophrenia, suggesting potential benefits for cariprazine in treating cognitive symptoms.

The oDGal Mouse: A Novel, Physiologically Relevant Rodent Model of Sporadic Alzheimer's Disease.

Sporadic Alzheimer's disease (sAD) represents a serious and growing worldwide economic and healthcare burden. Almost 95% of current AD patients are associated with sAD as opposed to patients presenting with well-characterized genetic mutations that lead to AD predisposition, i.e., familial AD (fAD). Presently, the use of transgenic (Tg) animals overexpressing human versions of these causative fAD genes represents the dominant research model for AD therapeutic development. As significant differences in etiology exist between sAD and fAD, it is perhaps more appropriate to develop novel, more sAD-reminiscent experimental models that would expedite the discovery of effective therapies for the majority of AD patients. Here we present the oDGal mouse model, a novel model of sAD that displays a range of AD-like pathologies as well as multiple cognitive deficits reminiscent of AD symptomology. Hippocampal cognitive impairment and pathology were delayed with N-acetyl-cysteine (NaC) treatment, which strongly suggests that reactive oxygen species (ROS) are the drivers of downstream pathologies such as elevated amyloid beta and hyperphosphorylated tau. These features demonstrate a desired pathophenotype that distinguishes our model from current transgenic rodent AD models. A preclinical model that presents a phenotype of non-genetic AD-like pathologies and cognitive deficits would benefit the sAD field, particularly when translating therapeutics from the preclinical to the clinical phase.

COVID-19 real-world data for the US and lessons to reopen business.

This Pearl article recounts the story of a US corporation, Lennar, the nation's leading homebuilder, an essential function in the US (not allowed to lock down), when faced with the coronavirus disease 2019 (COVID-19) pandemic at the end of February 2020. The culture of the company, which allowed it to proceed safely, is one of cohesion, trust, teamwork, and respect for fellow humans. Theirs is a culture in which the safety, wellness, and health of the associates (employees) and the communities they serve is the number one priority. All associates wear a name badge with first name only, and all name badges share the same family name, Lennar. At Lennar, individual success means nothing, and collective success means everything. This is the story of how Lennar took control of the COVID-19 pandemic, metamorphosed itself into an even stronger organization, better suited to deal with COVID-19, and more importantly, optimally suited for the 21st century. The lessons learned not only were instrumental to Lennar but could also apply to any company eager to reopen their business.

High-power quasi-CW diode-pumped 750-nm AlGaAs VECSEL emitting a peak power of 29.6†W and an average power of 8.5†W.

A peak output power of 29.6 W and an average output power of 8.5 W at a wavelength of 750 nm were demonstrated in quasi-CW multi-mode operation using an AlGaAs-based vertical external-cavity surface-emitting laser (VECSEL) diode-pumped at a wavelength of 675 nm. The comparatively low bandgap of the barrier material that was tuned to the pump-photon energy allowed a good compromise between low heat generation due to the quantum defect and strong absorptance of the pump radiation. The limitations for the average output power came mainly from insufficient heat flow from the intra-cavity heat spreader to the heat sink. These results show the potential for power scaling of diode-pumped VECSELs and the importance of effective heat removal.

Immunosuppression Profile of CFZ533 (Iscalimab), a Non-Depleting Anti-CD40 Antibody, and the Presence of Opportunistic Infections in a Rhesus Monkey Toxicology Study.

CFZ533 (iscalimab) is a nondepleting anti-CD40 antibody intended for inhibition of transplant organ rejection and treatment of autoimmune diseases. In a safety assessment in rhesus monkeys, CFZ533 was administered for 13 weeks up to 150 mg/kg/week subcutaneously. CFZ533 was shown previously to completely inhibit primary and secondary T-cell-dependent antibody responses. CD40 is expressed on B cells, antigen-presenting cells, and endothelial and epithelial cells, but is not expressed on T cells. Here, we demonstrate the complete suppression of germinal center formation in lymphoid organs. CFZ533 was well tolerated and did not cause any dose-limiting toxicity. However, the histological evaluation revealed increased numbers of CD4+ and CD8+ T cells in the T-cell-rich areas of lymph nodes enlarged in response to observed adenovirus and Cryptosporidium infections which suggest that T-cell immune function was unaffected. Background infections appear as the condition leading to unraveling the differential immunosuppressive effects by CFZ533. The presence of T cells at lymph nodes draining sites of infections corroborates the immunosuppressive mechanism, which is different from calcineurin-inhibiting drugs. Furthermore, CFZ533 did not show any hematological or microscopic evidence of thromboembolic events in rhesus monkeys, which were previously shown to respond with thromboembolism to treatment with anti-CD154 antibodies.

lab.js: A free, open, online study builder.

Web-based data collection is increasingly popular in both experimental and survey-based research because it is flexible, efficient, and location-independent. While dedicated software for laboratory-based experimentation and online surveys is commonplace, researchers looking to implement experiments in the browser have, heretofore, often had to manually construct their studies' content and logic using code. We introduce lab.js, a free, open-source experiment builder that makes it easy to build studies for both online and in-laboratory data collection. Through its visual interface, stimuli can be designed and combined into a study without programming, though studies' appearance and behavior can be fully customized using HTML, CSS, and JavaScript code if required. Presentation and response times are kept and measured with high accuracy and precision heretofore unmatched in browser-based studies. Experiments constructed with lab.js can be run directly on a local computer and published online with ease, with direct deployment to cloud hosting, export to web servers, and integration with popular data collection platforms. Studies can also be shared in an editable format, archived, re-used and adapted, enabling effortless, transparent replications, and thus facilitating open, cumulative science. The software is provided free of charge under an open-source license; further information, code, and extensive documentation are available from https://lab.js.org/ .

Evaluation of exosome derivatives as bio-informational reprogramming therapy for cancer.

Exosomes are nanoparticle sized (100 ± 50 nm) extracellular vesicles (ECVs) that play important roles in cell-to-cell communication. They do this by utilizing their natural ability to shuttle signaling molecules across the cellular microenvironment and promote paracrine signaling. Currently, exosomes are being explored for their potential as therapeutic agents for various degenerative diseases including cancer. The rationale behind their therapeutic ability is that they can transfer signaling biomolecules, and subsequently induce metabolic and physiological changes in diseased cells and tissues. In addition, exosomes can be used as a drug delivery system and may be very effective at reducing toxicity and increasing bioavailability of therapeutic molecules and drugs. Although exosomes were first believed to be a waste product of the cell, current research has demonstrated that these particles can serve as modulators of the immune system, act as cancer biomarkers, cause re-differentiation of cancer cells, and induce apoptosis in diseased cells. Extensive research has been performed specifically using amniotic fluid-derived extracellular vesicles, named "cytosomes". While the use of cytosomes in clinical application is still in the early stages, researchers have shown great potential for these EVs in regenerative medicine as immune modulators, in controlling microbial infection and by inducing tissue repair through the activation of endogenous, tissue-specific stem cells. This review emphasizes the capabilities of specific subsets of extracellular vesicles that can potentially be used for cancer therapy, principally as a source of bi-informational reprogramming for malignant cells.

PDGFRA defines the mesenchymal stem cell Kaposi's sarcoma progenitors by enabling KSHV oncogenesis in an angiogenic environment.

Kaposi's sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (Pα(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis. This is because growth in KS-like conditions generates a de-repressed KSHV epigenome allowing oncogenic KSHV gene expression in infected Pα(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected Pα(+)S MSCs to overcome KSHV-driven oncogene-induced senescence and cell cycle arrest via a PDGFRA-signaling mechanism; thus identifying PDGFRA not only as a phenotypic determinant for KS-progenitors but also as a critical enabler for viral oncogenesis.

A Cyclometalated NHC Iridium Complex Bearing a Cationic (η5 -Cyclopentadienyl)(η6 -phenyl)iron Backbone*.

Nucleophilic substitution of [(η5 -cyclopentadienyl)(η6 -chlorobenzene)iron(II)] hexafluorophosphate with sodium imidazolate resulted in the formation of [(η5 -cyclopentadienyl)(η6 -phenyl)iron(II)]imidazole hexafluorophosphate. The corresponding dicationic imidazolium salt, which was obtained by treating this imidazole precursor with methyl iodide, underwent cyclometallation with bis[dichlorido(η5 -1,2,3,4,5-pentamethylcyclopentadienyl]iridium(III) in the presence of triethyl amine. The resulting bimetallic iridium(III) complex is the first example of an NHC complex bearing a cationic and cyclometallated [(η5 -cyclopentadienyl)(η6 -phenyl)iron(II)]+ substituent. As its iron(II) precursors, the bimetallic iridium(III) complex was fully characterized by means of spectroscopy, elemental analysis and single crystal X-ray diffraction. In addition, it was investigated in a catalytic study, wherein it showed high activity in transfer hydrogenation compared to its neutral analogue having a simple phenyl instead of a cationic [(η5 -cyclopentadienyl)(η6 -phenyl)iron(II)]+ unit at the NHC ligand.

Stellate ganglion block combined with intra-arterial treatment: a "one-stop shop" for cerebral vasospasm after aneurysmal subarachnoid hemorrhage-a pilot study.

PURPOSE: Delayed cerebral ischemia (DCI) is a frequent cause of morbidity and mortality in patients with cerebral vasospasm (CV) following aneurysmal subarachnoid hemorrhage (aSAH). Refractory CV remains challenging to treat and often leads to permanent deficits and death despite aggressive therapy. We hereby report the feasibility and safety of stellate ganglion block (SGB) performed with a vascular roadmap-guided technique to minimize the risk of accidental vascular puncture and may be coupled to a diagnostic or therapeutic cerebral angiography. METHODS: In addition to a detailed description of the technique, we performed a retrospective analysis of a series of consecutive patients with refractory CV after aSAH that were treated with adjuvant roadmap-guided SGB. Clinical outcomes at discharge are reported. RESULTS: Nineteen SGB procedures were performed in 10 patients, after failure of traditional hemodynamic and endovascular treatments. Each patient received 1 to 3 SGB, usually interspaced by 24 h. In 4 patients, an indwelling microcatheter for continuous infusion was inserted. First SGB occurred on average 7.3 days after aSAH. SGB was coupled to intra-arterial nimodipine infusion or balloon angioplasty in 9 patients. SGB was technically successful in all patients. There were no technical or clinical complications. CONCLUSION: Adjuvant SGB may be coupled to endovascular therapy to treat refractory cerebral vasopasm within the same session. To guide needle placement, using a roadmap of the supra-aortic arteries may decrease the risk of complications. More prospective data is needed to evaluate the therapeutic efficacy, durability, and safety of SGB compared with the established standard of care.

Arterial collateral anatomy predicts the risk for intra-operative changes in somatosensory evoked potentials in patients undergoing carotid endarterectomy: a prospective cohort study.

BACKGROUND: During carotid endarterectomy (CEA), significant amplitude decrement of somatosensory evoked potentials (SEPs) is associated with post-operative neurological deficits. OBJECTIVE: To investigate the association between an incomplete circle of Willis and/or contralateral ICA occlusion and subsequent changes in intra-operatively monitored SEPs. METHODS: We performed a retrospective analysis of a single center, prospective cohort of consecutive patients undergoing CEA over a 42-month period after reviewing the collateral arterial anatomy on pre-operative radiological imaging. The primary endpoint was an intra-operative decline in SEPs > 50% compared to the baseline value during arterial cross-clamping. Univariate and multivariate logistic regression analyses were performed to investigate a potential association between contralateral ICA occlusion, incomplete circle of Willis, and subsequent alteration in SEPs. RESULTS: A total of 140 consecutive patients were included, of which 116 patients (82.9%) had symptomatic carotid stenosis of at least 50% according to the classification used in the North American Carotid Surgery Trial (NASCET) (Stroke 22:711-720, 1991). Six patients (4.3%) showed contralateral ICA occlusion, 22 patients (16%) a missing/hypoplastic anterior communicating artery (Acom) or A1 segment, and 79 patients (56%) a missing ipsilateral posterior communicating artery (Pcom) or P1 segment. ICA occlusion and missing segments of the anterior circulation (missing A1 and/or missing Acom) were associated with the primary endpoint (p = 0.003 and p = 0.022, respectively). CONCLUSION: Contralateral ICA occlusion and missing anterior collaterals of the circle of Willis increase the risk of intra-operative SEP changes during CEA. Pre-operative assessment of collateral arterial anatomy might help identifying patients with an increased intra-operative risk.

Effect of Steady and Dynamic Blood Pressure Parameters During Thrombectomy According to the Collateral Status.

Background and Purpose- Guidelines regarding blood pressure (BP) management during endovascular therapy (EVT) for anterior circulation strokes are questionable since the optimal BP target is a matter of debate. To evaluate the importance of hemodynamic control during EVT, we investigated the impact of dynamic and steady BP parameters during EVT on functional outcome (part 1) and according to the collateral status (CS; part 2). Methods- We performed a post hoc analysis of the ASTER trial (Contact Aspiration Versus Stent Retriever for Successful Recanalization). BP was measured noninvasively during EVT and CS assessed on the angiographic run before EVT. We studied dynamic BP parameter using BP variability (coefficient of variation) and steady BP parameter (hypotension time defined as systolic BP <140 mm Hg and mean arterial pressure <90 mm Hg). The primary outcome was favorable outcome defined as a 3-month modified Rankin Scale score between 0 and 2. Results- Among the 381 patients of the ASTER study, 172 patients were included in part 1 and 159 in part 2. Systolic BP, diastolic BP, and mean arterial pressure variability were negatively associated with favorable outcome regardless of CS: per 10-unit increase, adjusted odds ratios were 0.45 (95% CI, 0.20-0.98), 0.37 (95% CI, 0.19-0.72), and 0.35 (95% CI, 0.16-0.76), respectively. According to CS, the hypotension time with periprocedural mean arterial pressure <90 mm Hg was negatively associated with favorable outcome in patients with poor CS (adjusted odds ratio, 0.88 [95% CI, 0.72-1.09]) but not in patients with good CS (adjusted odds ratio, 1.24 [95% CI, 0.91-1.67]; Phet=0.047). Conclusions- The CS did not modify the association between dynamic parameters and functional outcomes, but some findings suggest that the CS modifies the association between steady parameter and functional outcomes. Hypotension time according to the CS was not statistically predictive of poor outcomes but displayed a trend toward worse outcomes for patients with poor CS only.

Effect of Pre- and In-Hospital Delay on Reperfusion in Acute Ischemic Stroke Mechanical Thrombectomy.

BACKGROUND AND PURPOSE: Post hoc analyses of randomized controlled clinical trials evaluating mechanical thrombectomy have suggested that admission-to-groin-puncture (ATG) delays are associated with reduced reperfusion rates. Purpose of this analysis was to validate this association in a real-world cohort and to find associated factors and confounders for prolonged ATG intervals. METHODS: Patients included into the BEYOND-SWIFT cohort (Bernese-European Registry for Ischemic Stroke Patients Treated Outside Current Guidelines With Neurothrombectomy Devices Using the Solitaire FR With the Intention for Thrombectomy; https://www.clinicaltrials.gov; Unique identifier: NCT03496064) were analyzed (n=2386). Association between baseline characteristics and ATG was evaluated using mixed linear regression analysis. The effect of increasing symptom-onset-to-admission and ATG intervals on successful reperfusion (defined as Thrombolysis in Cerebral Infarction [TICI] 2b-3) was evaluated using logistic regression analysis adjusting for potential confounders. RESULTS: Median ATG was 73 minutes. Prolonged ATG intervals were associated with the use of magnetic resonance imaging (+19.1 [95% CI, +9.1 to +29.1] minutes), general anesthesia (+12.1 [95% CI, +3.7 to +20.4] minutes), and borderline indication criteria, such as lower National Institutes of Health Stroke Scale, late presentations, or not meeting top-tier early time window eligibility criteria (+13.8 [95% CI, +6.1 to +21.6] minutes). There was a 13% relative odds reduction for TICI 2b-3 (adjusted odds ratio [aOR], 0.87 [95% CI, 0.79-0.96]) and TICI 2c/3 (aOR, 0.87 [95% CI, 0.79-0.95]) per hour ATG delay, while the reduction of TICI 2b-3 per hour increase symptom-onset-to-admission was minor (aOR, 0.97 [95% CI, 0.94-0.99]) and inconsistent regarding TICI 2c/3 (aOR, 0.99 [95% CI, 0.97-1.02]). After adjusting for identified factors associated with prolonged ATG intervals, the association of ATG delay and lower rates of TICI 2b-3 remained tangible (aOR, 0.87 [95% CI, 0.76-0.99]). CONCLUSIONS: There is a great potential to reduce ATG, and potential targets for improvement can be deduced from observational data. The association between in-hospital delay and reduced reperfusion rates is evident in real-world clinical data, underscoring the need to optimize in-hospital workflows. Given the only minor association between symptom-onset-to-admission intervals and reperfusion rates, the causal relationship of this association warrants further research. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03496064.

Endovascular Stroke Treatment and Risk of Intracranial Hemorrhage in Anticoagulated Patients.

Background and Purpose- We aimed to determine the safety and mortality after mechanical thrombectomy in patients taking vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). Methods- In a multicenter observational cohort study, we used multiple logistic regression analysis to evaluate associations of symptomatic intracranial hemorrhage (sICH) with VKA or DOAC prescription before thrombectomy as compared with no anticoagulation. The primary outcomes were the rate of sICH and all-cause mortality at 90 days, incorporating sensitivity analysis regarding confirmed therapeutic anticoagulation. Additionally, we performed a systematic review and meta-analysis of literature on this topic. Results- Altogether, 1932 patients were included (VKA, n=222; DOAC, n=98; no anticoagulation, n=1612); median age, 74 years (interquartile range, 62-82); 49.6% women. VKA prescription was associated with increased odds for sICH and mortality (adjusted odds ratio [aOR], 2.55 [95% CI, 1.35-4.84] and 1.64 [95% CI, 1.09-2.47]) as compared with the control group, whereas no association with DOAC intake was observed (aOR, 0.98 [95% CI, 0.29-3.35] and 1.35 [95% CI, 0.72-2.53]). Sensitivity analyses considering only patients within the confirmed therapeutic anticoagulation range did not alter the findings. A study-level meta-analysis incorporating data from 7462 patients (855 VKAs, 318 DOACs, and 6289 controls) from 15 observational cohorts corroborated these observations, yielding an increased rate of sICH in VKA patients (aOR, 1.62 [95% CI, 1.22-2.17]) but not in DOAC patients (aOR, 1.03 [95% CI, 0.60-1.80]). Conclusions- Patients taking VKA have an increased risk of sICH and mortality after mechanical thrombectomy. The lower risk of sICH associated with DOAC may also be noticeable in the acute setting. Improved selection might be advisable in VKA-treated patients. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03496064. Systematic Review and Meta-Analysis: CRD42019127464.

Intracranial Arteriovenous Malformation: Cinematic Rendering with Digital Subtraction Angiography.

Online supplemental material is available for this article.

KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis.

Kaposi's sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predominantly-activated RTK in KSHV-induced mouse KS-tumors. We show that: 1) KSHV lytic replication and the vGPCR can activate PDGFRA through upregulation of its ligands PDGFA/B, which increase c-myc, VEGF and KSHV gene expression in infected cells 2) KSHV infected spindle cells of most AIDS-KS lesions display robust phospho-PDGFRA staining 3) blocking PDGFRA-signaling with N-acetyl-cysteine, RTK-inhibitors Imatinib and Sunitinib, or dominant-negative PDGFRA inhibits tumorigenesis 4) PDGFRA D842V activating-mutation confers resistance to Imatinib in mouse-KS tumorigenesis. Our data show that KSHV usurps sarcomagenic PDGFRA signaling to drive KS. This and the fact that PDGFRA drives non-viral sarcomas highlights the importance for KSHV-induced ligand-mediated activation of PDGFRA in KS sarcomagenesis and shows that this oncogenic axis could be successfully blocked to impede KS tumor growth.

Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8+ T cell-mediated macrophage death.

Aims: The E3-ligase CBL-B (Casitas B-cell lymphoma-B) is an important negative regulator of T cell activation that is also expressed in macrophages. T cells and macrophages mediate atherosclerosis, but their regulation in this disease remains largely unknown; thus, we studied the function of CBL-B in atherogenesis. Methods and results: The expression of CBL-B in human atherosclerotic plaques was lower in advanced lesions compared with initial lesions and correlated inversely with necrotic core area. Twenty weeks old Cblb-/-Apoe-/- mice showed a significant increase in plaque area in the aortic arch, where initial plaques were present. In the aortic root, a site containing advanced plaques, lesion area rose by 40%, accompanied by a dramatic change in plaque phenotype. Plaques contained fewer macrophages due to increased apoptosis, larger necrotic cores, and more CD8+ T cells. Cblb-/-Apoe-/- macrophages exhibited enhanced migration and increased cytokine production and lipid uptake. Casitas B-cell lymphoma-B deficiency increased CD8+ T cell numbers, which were protected against apoptosis and regulatory T cell-mediated suppression. IFNγ and granzyme B production was enhanced in Cblb-/-Apoe-/- CD8+ T cells, which provoked macrophage killing. Depletion of CD8+ T cells in Cblb-/-Apoe-/- bone marrow chimeras rescued the phenotype, indicating that CBL-B controls atherosclerosis mainly through its function in CD8+ T cells. Conclusion: Casitas B-cell lymphoma-B expression in human plaques decreases during the progression of atherosclerosis. As an important regulator of immune responses in experimental atherosclerosis, CBL-B hampers macrophage recruitment and activation during initial atherosclerosis and limits CD8+ T cell activation and CD8+ T cell-mediated macrophage death in advanced atherosclerosis, thereby preventing the progression towards high-risk plaques.

Structure, development, and functional morphology of the cement gland of the giant danio, Devario malabaricus.

BACKGROUND: Aquatic species in several clades possess cement glands producing adhesive secretions of various strengths. In vertebrates, transient adhesive organs have been extensively studied in Xenopus laevis, other anurans, and in several fish species. However, the development of these structures is not fully understood. RESULTS: Here, we report on the development and functional morphology of the adhesive gland of a giant danio species, Devario malabaricus. We found that the gland is localized on the larval head, is composed of goblet-like secretory cells framed by basal, bordering, and intercalated apical epithelial cells, and is innervated by the trigeminal ganglion. The gland allows nonswimming larvae to adhere to various substrates. Its secretory cells differentiate by 12 hours postfertilization and begin to disappear in the second week of life. Exogenous retinoic acid disrupts the gland's patterning. More importantly, the single mature gland emerges from fusion of two differentiated secretory cells fields; this fusion is dependent on nonmuscle myosin II function. CONCLUSIONS: Taken together, our studies provide the first documentation of the embryonic development, structure, and function of the adhesive apparatus of a danioninae. To our knowledge, this is also the first report of a cement gland arising from convergence of two bilateral fields.