Emerging Two-Dimensional Conductivity at the Interface between Mott and Band Insulators.

Intriguingly, conducting perovskite interfaces between ordinary band insulators are widely explored, whereas similar interfaces with Mott insulators are still not quite understood. Here, we address the (001), (110), and (111) interfaces between the LaTiO_{3} Mott, and large band gap KTaO_{3} insulators. Based on first-principles calculations, we reveal a mechanism of interfacial conductivity, which is distinct from a formerly studied one applicable to interfaces between polar wideband insulators. Here, the key factor causing conductivity is the matching of oxygen octahedra tilting in KTaO_{3} and LaTiO_{3} which, due to a small gap in the LaTiO_{3} results in its sensitivity to the crystal structure, yields metallization of its overlayer and following charge transfer from Ti to Ta. Our findings, also applicable to other Mott insulators interfaces, shed light on the emergence of conductivity observed in LaTiO_{3}/KTaO_{3} (110) where the "polar" arguments are not applicable and on the emergence of superconductivity in these structures.

ARF6 is a host factor for SARS-CoV-2 infection in vitro.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged beta-coronavirus that enter cells via two routes, direct fusion at the plasma membrane or endocytosis followed by fusion with the late endosome/lysosome. While the viral receptor, ACE2, multiple entry factors and the mechanism of fusion of the virus at the plasma membrane have been investigated extensively, viral entry via the endocytic pathway is less understood. By using a human hepatocarcinoma cell line, Huh-7, which is resistant to the antiviral action of the TMPRSS2 inhibitor camostat, we discovered that SARS-CoV-2 entry is not dependent on dynamin but on cholesterol. ADP-ribosylation factor 6 (ARF6) has been described as a host factor for SARS-CoV-2 replication and is involved in the entry and infection of several pathogenic viruses. Using CRISPR/Cas9 genetic deletion, a modest reduction in SARS-CoV-2 uptake and infection in Huh-7 was observed. In addition, pharmacological inhibition of ARF6 with the small molecule NAV-2729 showed a dose-dependent reduction of viral infection. Importantly, NAV-2729 also reduced SARS-CoV-2 viral loads in more physiological models of infection: Calu-3 cells and kidney organoids. This highlighted a role for ARF6 in multiple cell contexts. Together, these experiments point to ARF6 as a putative target to develop antiviral strategies against SARS-CoV-2.

Solitons in Inhomogeneous Gauge Potentials: Integrable and Nonintegrable Dynamics.

We introduce an exactly integrable nonlinear model describing the dynamics of spinor solitons in space-dependent matrix gauge potentials of rather general types. The model is shown to be gauge equivalent to the integrable system of vector nonlinear Schrödinger equations known as the Manakov model. As an example we consider a self-attractive Bose-Einstein condensate with random spin-orbit coupling (SOC). If Zeeman splitting is also included, the system becomes nonintegrable. We illustrate this by considering the random walk of a soliton in a disordered SOC landscape. While at zero Zeeman splitting the soliton moves without scattering along linear trajectories in the random SOC landscape; at nonzero splitting it exhibits strong scattering by the SOC inhomogeneities. For a large Zeeman splitting, the integrability is restored. In this sense, the Zeeman splitting serves as a parameter controlling the crossover between two different integrable limits.

Chaotization of internal motion of excitons in ultrathin layers by spin-orbit coupling.

We show that Rashba spin-orbit coupling (SOC) can generate chaotic behavior of excitons in two-dimensional semiconductor structures. To model this chaos, we study a Kepler system with spin-orbit coupling and numerically obtain a transition to chaos at a sufficiently strong coupling. The chaos emerges since the SOC reduces the number of integrals of motion as compared to the number of degrees of freedom. Dynamically, the dependence of the exciton energy on the spin orientation in the presence of SOC produces an anomalous spin-dependent velocity resulting in chaotic motion. We observe numerically the critical dependence of the dynamics on the initial conditions, where the system can return to and exit a stability domain through very small changes in the initial spin orientation. This chaos can have a strong influence on the lifetime of optically injected carriers in semiconductors and organometallic perovskites. Hence, this effect should be taken into account while designing structures for photovoltaic and optical spintronics applications, where excitons play a significant role.

A phase II study of temsirolimus added to low-dose weekly carboplatin and paclitaxel for patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

Background: Activating events along the PI3K/mTOR pathway are common in head and neck squamous cell carcinomas (HNSCC), and preclinical studies suggest additive or synergistic effects when combining mTORC1 inhibitors with carboplatin and paclitaxel chemotherapy. Patients and methods: In this single-institution phase II study, the combination of temsirolimus 25 mg, carboplatin AUC 1.5, and paclitaxel 80 mg/m2 administered on days 1 and 8 of a 21-day cycle was evaluated in 36 patients with recurrent and/or metastatic (R/M) HNSCC. The primary end point was objective response rate after two cycles of treatment. Secondary end points include the safety and tolerability profile and overall survival. Correlative studies with exome mutational analysis were performed in pre-treatment biopsy samples from 21 patients. Results: Fifteen (41.7%) patients had an objective response, which were all partial responses, and 19 (52.3%) patients had stable disease as best response. The two patients who were designated as 'non-responders' were removed from study prior to two cycles of treatment, but are included in the efficacy and safety analyses. The median duration on study was 5.3 months and the median progression-free survival and overall survival were 5.9 months (95% confidence interval, 4.8-7.1) and 12.8 months (95% confidence interval, 9.8-15.8), respectively. The most common grade 3 and 4 adverse events were hematologic toxicities. Three (3.8%) patients developed neutropenic fever on study. Three of four patients with PIK3CA mutations experienced tumor regressions, and responses were also seen in patients with other genetic alterations in the PI3K/mTOR pathway. Conclusion: The combination of temsirolimus with low-dose weekly carboplatin and paclitaxel appears to have meaningful clinical efficacy in the treatment of R/M HNSCC. This regimen has a relatively high response rate compared to other treatments evaluated in R/M HNSCC, and potential associations with genetic alterations in the PI3K/mTOR pathway should be further explored.

Oncologist use and perception of large panel next-generation tumor sequencing.

BACKGROUND: Genomic profiling is increasingly incorporated into oncology research and the clinical care of cancer patients. We sought to determine physician perception and use of enterprise-scale clinical sequencing at our center, including whether testing changed management and the reasoning behind this decision-making. PATIENTS AND METHODS: All physicians who consented patients to MSK-IMPACT, a next-generation hybridization capture assay, in tumor types where molecular profiling is not routinely performed were asked to complete a questionnaire for each patient. Physician determination of genomic 'actionability' was compared to an expertly curated knowledgebase of somatic variants. Reported management decisions were compared to chart review. RESULTS: Responses were received from 146 physicians pertaining to 1932 patients diagnosed with 1 of 49 cancer types. Physicians indicated that sequencing altered management in 21% (331/1593) of patients in need of a treatment change. Among those in whom treatment was not altered, physicians indicated the presence of an actionable alteration in 55% (805/1474), however, only 45% (362/805) of these cases had a genomic variant annotated as actionable by expert curators. Further evaluation of these patients revealed that 66% (291/443) had a variant in a gene associated with biologic but not clinical evidence of actionability or a variant of unknown significance in a gene with at least one known actionable alteration. Of the cases annotated as actionable by experts, physicians identified an actionable alteration in 81% (362/445). In total, 13% (245/1932) of patients were enrolled to a genomically matched trial. CONCLUSION: Although physician and expert assessment differed, clinicians demonstrate substantial awareness of the genes associated with potential actionability and report using this knowledge to inform management in one in five patients. CLINICAL TRIAL NUMBER: NCT01775072.

A phase II study of axitinib (AG-013736) in patients with incurable adenoid cystic carcinoma.

BACKGROUND: Recurrent/metastatic adenoid cystic carcinoma (ACC) is an incurable disease with no standard treatments. The majority of ACCs express the oncogenic transcription factor MYB (also c-myb), often in the context of a MYB gene rearrangement. This phase II trial of the tyrosine kinase inhibitor (TKI) axitinib (Pfizer) tested the hypothesis that targeting pathways activated by MYB can be therapeutically effective for ACC. PATIENTS AND METHODS: This is a minimax two-stage, phase II trial that enrolled patients with incurable ACC of any primary site. Progressive or symptomatic disease was required. Patients were treated with axitinib 5 mg oral twice daily; dose escalation was allowed. The primary end point was best overall response (BOR). An exploratory analysis correlating biomarkers to drug benefit was conducted, including next-generation sequencing (NGS) in 11 patients. RESULTS: Thirty-three patients were registered and evaluable for response. Fifteen patients had the axitinib dose increased. Tumor shrinkage was achieved in 22 (66.7%); 3 (9.1%) had confirmed partial responses. Twenty-five (75.8%) patients had stable disease, 10 of whom had disease stability for >6 months. The median progression-free survival (PFS) was 5.7 months (range 0.92-21.8 months). Grade 3 axitinib-related toxicities included hypertension, oral pain and fatigue. A trend toward superior PFS was noted with the MYB/NFIB rearrangement, although this was not statistically significant. NGS revealed three tumors with 4q12 amplification, producing increased copies of axitinib-targeted genes PDGFR/KDR/KIT. Two 4q12 amplified patients achieved stable disease for >6 months, including one with significant tumor reduction and the longest PFS on study (21.8 months). CONCLUSIONS: Although the primary end point was not met, axitinib exhibited clinical activity with tumor shrinkage achieved in the majority of patients with progressive disease before trial enrollment. Analysis of MYB biomarkers and genomic profiling suggests the hypothesis that 4q12 amplified ACCs are a disease subset that benefit from TKI therapy.

Evidence supporting the 19 ß-strand model for Tom40 from cysteine scanning and protease site accessibility studies.

Most proteins found in mitochondria are translated in the cytosol and enter the organelle via the TOM complex (translocase of the outer mitochondrial membrane). Tom40 is the pore forming component of the complex. Although the three-dimensional structure of Tom40 has not been determined, the structure of porin, a related protein, has been shown to be a ß-barrel containing 19 membrane spanning ß-strands and an N-terminal α-helical region. The evolutionary relationship between the two proteins has allowed modeling of Tom40 into a similar structure by several laboratories. However, it has been suggested that the 19-strand porin structure does not represent the native form of the protein. If true, modeling of Tom40 based on the porin structure would also be invalid. We have used substituted cysteine accessibility mapping to identify several potential ß-strands in the Tom40 protein in isolated mitochondria. These data, together with protease accessibility studies, support the 19 ß-strand model for Tom40 with the C-terminal end of the protein localized to the intermembrane space.

Effect of resistance training on neuromuscular junctions of young and aged muscles featuring different recruitment patterns.

To examine the effects of aging on neuromuscular adaptations to resistance training (i.e., weight lifting), young (9 months of age) and aged (20 months of age) male rats either participated in a 7-week ladder climbing protocol with additional weight attached to their tails or served as controls (n = 10/group). At the conclusion, rats were euthanized and hindlimb muscles were quickly removed and frozen for later analysis. Longitudinal sections of the soleus and plantaris muscles were collected, and pre- and postsynaptic features of neuromuscular junctions (NMJs) were visualized with immunofluorescence staining procedures. Cross-sections of the same muscles were histochemically stained to determine myofiber profiles (fiber type and size). Statistical analysis was by two-way ANOVA (main effects of age and treatment) with significance set at P ≤ 0.05. Results revealed that training-induced remodeling of NMJs was evident only at the postsynaptic endplate region of soleus fast-twitch myofibers. In contrast, aging was associated with pre- and postsynaptic remodeling in fast- and slow-twitch myofibers of the plantaris. Although both the soleus and the plantaris muscles failed to display either training or aging-related alterations in myofiber size, aged plantaris muscles exhibited an increased expression of type I (slow-twitch) myofibers in conjunction with a reduced percentage of type II (fast-twitch) myofibers, suggesting early stages of sarcopenia. These data demonstrate the high degree of specificity of synaptic modifications made in response to exercise and aging and that the sparsely recruited plantaris is more vulnerable to the effects of aging than the more frequently recruited soleus muscle.

Dynamics of Spin-Orbit Coupled Bose-Einstein Condensates in a Random Potential.

Disorder plays a crucial role in spin dynamics in solids and condensed matter systems. We demonstrate that for a spin-orbit coupled Bose-Einstein condensate in a random potential two mechanisms of spin evolution that can be characterized as "precessional" and "anomalous" are at work simultaneously. The precessional mechanism, typical for solids, is due to the condensate displacement. The unconventional anomalous mechanism is due to the spin-dependent velocity producing the distribution of the condensate spin polarization. The condensate expansion is accompanied by a random displacement and fragmentation, where it becomes sparse, as clearly revealed in the spin dynamics. Thus, different stages of the evolution can be characterized by looking at the condensate spin.

Phase I study of weekly nab-paclitaxel + weekly cetuximab + intensity-modulated radiation therapy (IMRT) in patients with stage III-IVB head and neck squamous cell carcinoma (HNSCC).

BACKGROUND: There is a clinical need to improve the efficacy of standard cetuximab + concurrent intensity-modulated radiation therapy (IMRT) for patients with locally and/or regionally advanced HNSCC. Taxanes have radiosensitizing activity against HNSCC, and nab-paclitaxel may offer therapeutic advantage in comparison with other taxanes. PATIENTS AND METHODS: This was a single-institution phase I study with a modified 3 + 3 design. Four dose levels (DLs) of weekly nab-paclitaxel were explored (30, 45, 60, and 80 mg/m(2)), given with standard weekly cetuximab (450 mg/m(2) loading dose followed by 250 mg/m(2) weekly) and concurrent IMRT (total dose, 70 Gy). RESULTS: Twenty-five eligible patients (20 M, 5 F) enrolled, with median age 58 years (range, 46-84 years). Primary tumor sites were oropharynx, 19 (10 human papillomavirus [HPV] pos, 8 HPV neg, 1 not done); neck node with unknown primary, 2; larynx 2; and oral cavity and maxillary sinus, 1 each. Seven patients had received prior induction chemotherapy. Maximum tolerated dose (MTD) was exceeded at DL4 (nab-paclitaxel, 80 mg/m(2)) with three dose-limiting toxicities (DLTs) (grade 3 neuropathy, grade 3 dehydration, with grade 3 mucositis grade 3 anemia) among five assessable patients. There was only one DLT (grade 3 supraventricular tachycardia) among six patients at DL3 (nab-paclitaxel, 60 mg/m(2)), and this was deemed the MTD. Among 23 assessable patients, the most common ≥ g3 AEs were lymphopenia 100%, functional mucositis 65%, and pain in throat/oral cavity 52%. At a median follow-up of 33 months, 2-year failure-free survival (FFS) is 65% [95% confidence interval (CI) 42% to 81%] and 2-year overall survival (OS) is 91% (95% CI 69-97). CONCLUSION: The recommended phase II dose for nab-paclitaxel is 60 mg/m(2) weekly when given standard weekly cetuximab and concurrent IMRT. This regimen merits further study as a nonplatinum alternative to IMRT + cetuximab alone. CLINICALTRIALSGOV ID: NCT00736619.

An evidence-based checklist to assess neuropsychological outcomes of epilepsy surgery: how good is the evidence?

PURPOSE: We aimed to assess the quality of evidence on neuropsychological outcomes after epilepsy surgery (ES). Accordingly, we created an evidence-based neuropsychology (EBNP) checklist to assess neuropsychological outcomes and applied this tool to studies from a systematic review. METHODS: The EBNP checklist was created using clinical expert input, scale development methodology for item generation and reduction and inter-rater reliability, and critical appraisal guidelines for studies about treatment. The checklist was applied to articles obtained through a systematic review of resective ES neuropsychological outcomes. The proportion of studies fulfilling the quality criteria and the total quality score were used to assess the quality of the evidence. RESULTS: An initial 45-item checklist was applied to 147 articles, with excellent inter-rater agreement (kappa=0.80). The mean quality score was 23 (SD: 4, range: 12-33). There was substantial variability in the percentage of studies meeting the criteria for specific items (0-99%). The median proportion of papers fulfilling various quality criteria was 1.4% for items related to group comparisons, 37% for clinical applicability, 67% for patient description, 78% for outcome assessment, and 91% for interventions. Higher quality correlated with longitudinal design, reporting presurgical IQ, seizure frequency and antiepileptic drugs, and using validated measures of change in individual patients. The final EBNP checklist consisted of 19 items. DISCUSSION: The EBNP checklist reliably identified quality strengths and threats to validity of neuropsychological outcome studies in ES. Studies would be most improved by the inclusion of random allocation to interventions or at minimum blinded outcome assessment, empirically based measures of reliable change and completeness of reporting of follow-up.

Safety and efficacy of cobimetinib plus atezolizumab in patients with solid tumors: a phase II, open-label, multicenter, multicohort study.

BACKGROUND: Although introduction of immune checkpoint inhibitors has revolutionized the treatment of cancer, their response rates are generally low. Preclinical and early phase clinical data suggest that MEK inhibition may sensitize tumors to immune checkpoint inhibitors by upregulating tumor antigen expression, programmed death-ligand 1 (PD-L1) expression, and tumor T-cell infiltration. We evaluated the efficacy and safety of cobimetinib plus atezolizumab in patients with advanced solid tumors in the open-label, multicohort phase II COTEST study. PATIENTS AND METHODS: This analysis of the COTEST trial included patients from cohorts 1-4 [1-3: anti-programmed cell death protein 1 (PD-1)/PD-L1 treatment-naive patients; 4: patients with disease progression on anti-PD-1/anti-PD-L1 treatment] who received cobimetinib 60 mg once daily for the first 21 days and intravenous infusions of atezolizumab 840 mg on days 1 and 15 of each 28-day cycle. Efficacy endpoints included objective response rate, overall survival, progression-free survival (PFS), and disease control rate. RESULTS: Overall, 77 patients were enrolled in cohorts 1-4 (78% male; median age 62.8 years). Objective response rate was 20% in cohort 1 [squamous cell carcinoma of the head and neck (SCCHN)], 30% in cohort 2 (urothelial carcinoma), and 18% in cohort 3 (renal cell carcinoma); there were no responders among 20 patients in cohort 4 (SCCHN). The disease control rates in cohorts 1-4 were 50%, 40%, 24%, and 25%, respectively. The median PFS was 5.5, 3.4, 3.4, and 3.6 months in cohorts 1-4, respectively, and the median overall survival was 16.8, 18.7, 21.7, and 7.7 months, respectively. Most adverse events were of grade 1/2 and were manageable. CONCLUSIONS: Cobimetinib plus atezolizumab had moderate activity in patients with anti-PD-1/PD-L1 treatment-naive SCCHN and urothelial carcinoma, and weak activity in anti-PD-1/PD-L1 treatment-naive renal cell carcinoma, and no activity in checkpoint inhibitor-treated patients.

Fast and robust spin manipulation in a quantum dot by electric fields.

We apply an invariant-based inverse engineering method to control, by time-dependent electric fields, the spin dynamics in a quantum dot with spin-orbit coupling in a weak magnetic field. The designed electric fields provide a shortcut to adiabatic processes that flip the spin rapidly, thus avoiding decoherence effects. This approach, being robust with respect to the device-dependent noise, can open new possibilities for spin-based quantum information processing.

Spin-flip transitions induced by time-dependent electric fields in surfaces with strong spin-orbit interaction.

We present a comprehensive theoretical investigation of the light absorption rate at a Pb/Ge(111)-ß√3 × âˆš3R30° surface with strong spin-orbit coupling. Our calculations show that electron spin-flip transitions cause as much as 6% of the total light absorption, representing 1 order of magnitude enhancement over Rashba-like systems. Thus, we demonstrate that a substantial part of the light irradiating this nominally nonmagnetic surface is attenuated in spin-flip processes. Remarkably, the spin-flip transition probability is structured in well-defined hot spots within the Brillouin zone, where the electron spin experiences a sudden 90° rotation. This mechanism offers the possibility of an experimental approach to the spin-orbit phenomena by optical means.

Nonlinear anomalous Hall effect and negative magnetoresistance in a system with random Rashba field.

We predict two spin-dependent transport phenomena in two-dimensional electron systems, which are induced by a spatially fluctuating Rashba spin-orbit interaction. When the electron gas is magnetized, the random Rashba interaction leads to the anomalous Hall effect. An example of such a system is a narrow-gap magnetic semiconductor-based symmetric quantum well. We show that the anomalous Hall conductivity reveals a strongly nonlinear dependence on the magnetization, decreasing exponentially at large spin density. We also show that electron scattering from a fluctuating Rashba field in a two-dimensional nonmagnetic electron system leads to a negative magnetoresistance arising solely due to spin-dependent effects.

Second-harmonic generation induced by electric currents in GaAs.

We demonstrate a new, nonlinear optical effect of electric currents. First, a steady current is generated by applying a voltage on a doped GaAs crystal. We demonstrate that this current induces second-harmonic generation of a probe laser pulse. Second, we optically inject a transient current in an undoped GaAs crystal by using a pair of ultrafast laser pulses and demonstrate that it induces the same second-harmonic generation. In both cases, the induced second-order nonlinear susceptibility is proportional to the current density. This effect can be used for nondestructive, noninvasive, and ultrafast imaging of currents. These advantages are illustrated by the real-time observations of a coherent plasma oscillation and spatial resolution of current distribution in a device. This new effect also provides a mechanism for electrical control of the optical response of materials.

Spin tunneling and manipulation in nanostructures.

The results for joint effects of tunneling and spin-orbit coupling on spin dynamics in nanostructures are presented for systems with discrete and continuous spectra. We demonstrate that tunneling plays the crucial role in the spin dynamics and the abilities of spin manipulation by external electric field. This result can be important for design of nanostructures-based spintronics devices.

ARF6 is a host factor for SARS-CoV-2 infection in vitro.

SARS-CoV-2 is a newly emerged beta-coronavirus that enter cells via two routes, direct fusion at the plasma membrane or endocytosis followed by fusion with the late endosome/lysosome. While the viral receptor, ACE2, multiple entry factors, and the mechanism of fusion of the virus at the plasma membrane have been extensively investigated, viral entry via the endocytic pathway is less understood. By using a human hepatocarcinoma cell line, Huh-7, which is resistant to the antiviral action of the TMPRSS2 inhibitor camostat, we discovered that SARS-CoV-2 entry is not dependent on dynamin but dependent on cholesterol. ADP-ribosylation factor 6 (ARF6) has been described as a host factor for SARS-CoV-2 replication and it is involved in the entry and infection of several pathogenic viruses. Using CRISPR-Cas9 genetic deletion, we observed that ARF6 is important for SARS-CoV-2 uptake and infection in Huh-7. This finding was corroborated using a pharmacologic inhibitor, whereby the ARF6 inhibitor NAV-2729 showed a dose-dependent inhibition of viral infection. Importantly, NAV-2729 reduced SARS-CoV-2 viral loads also in more physiologic models of infection: Calu-3 and kidney organoids. This highlighted the importance of ARF6 in multiple cell contexts. Together, these experiments points to ARF6 as a putative target to develop antiviral strategies against SARS-CoV-2.