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Ruth Percik,1– 3 Cecilie Oedegaard Smith,3,4 Anca Leibovici,5,6 Ayelet Shai7 1Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, Ramat Gan, Israel; 2Endo-Oncology Clinic, Sheba Medical Center, Ramat Gan, Israel; 3Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel; 4Oncology Institute, Sheba Medical Center, Ramat Gan, Israel; 5Oncology Department, Galilee Medical Center, Nahariya, Israel; 6Azrielly Faculty of Medicine, Bar-Ilan University, Zafed, Israel; 7Breast Cancer Unit, Division of Oncology, RAMBAM Health Care Campus, Haifa, IsraelCorrespondence: Ayelet Shai, Oncology Department, Rambam Health Care Campus, Ha’alia Hashnia 8, Haifa, 3109601, Israel, Tel +972507887731, Email a_shai@rambam.health.gov.ilAbstract: PIK3CA activating mutations are found in 40% of advanced breast cancer and are associated with worse prognosis. PI3K blockage is associated with insulin resistance, leading to hyperglycemia and hyperinsulinemia. Alpelisib is the first PI3K inhibitor used in cancer treatment. Laboratory evidence indicated that alpelisib-induced hyperinsulinemia offsets the drug’s efficacy, but insulin levels were not tested in the clinical trials that evaluated alpelisib for breast cancer. Hyperglycemia could also interfere with anti-tumor effects of PI3K inhibitors by inducing Immune tolerance and altered mitochondrial metabolism. We have monitored insulin levels in 4 breast cancer patients with concomitant metabolic syndrome treated with alpelisib, and pre-treated patients with baseline increased insulin levels with pioglitazone, a potent insulin sensitizer, to target both hyperinsulinemia and hyperglycemia, and we report the treatment course of these patients. All patients achieved glycemic control and were able to maintain alpelisib dose intensity. Duration of response to alpelisib was longer than anticipated in this treatment setting. Insulin dynamics confirmed the efficacy of pioglitazone as a specific on-target hypoglycemic and hypo-insulinemic agent in the unique setting of PI3K blockade. Our experience suggests that targeting hyperinsulinemia in patients with is safe and feasible and results in good metabolic and oncologic outcomes.Keywords: alpelisib, hyperglycemia, insulin, pioglitazone, hyperinsulinemia, diabetes mellitus

Nelarabine, an antimetabolite prodrug, is approved as monotherapy for children and adults with relapsed and refractory T-cell acute lymphoblastic leukemia and lymphoma (R/R T-ALL/LBL), although it is often used in combination regimens. We sought to understand differences in efficacy and toxicity when nelarabine is administered alone or in combination. We retrospectively analyzed 44 consecutive patients with R/R T-ALL/LBL; 29 of whom were treated with combination therapy, most with cyclophosphamide and etoposide (23, 79%) and 15 with monotherapy. The median age was 19 years (range, 2-69), including 18 children (

Photosynthetic organisms frequently experience abiotic stress that restricts their growth and development. Under such circumstances, most absorbed solar energy cannot be used for CO2 fixation and can cause the photoproduction of reactive oxygen species (ROS) that can damage the photosynthetic reaction centers of PSI and PSII, resulting in a decline in primary productivity. This work describes a biological “switch” in the green alga Chlamydomonas reinhardtii that reversibly restricts photosynthetic electron transport (PET) at the cytochrome b6f (Cyt b6f) complex when the capacity for accepting electrons downstream of PSI is severely limited. We specifically show this restriction in STARCHLESS6 (sta6) mutant cells, which cannot synthesize starch when they are limited for nitrogen (growth inhibition) and subjected to a dark-to-light transition. This restriction represents a form of photosynthetic control that causes diminished electron flow to PSI and thereby prevents PSI photodamage but does not appear to rely on a ΔpH. Furthermore, when electron flow is restricted, the plastid alternative oxidase (PTOX) becomes active, functioning as an electron valve that dissipates some excitation energy absorbed by PSII and allows the formation of a proton motive force (PMF) that would drive some ATP production (potentially sustaining PSII repair and nonphotochemical quenching [NPQ]). The restriction at the Cyt b6f complex can be gradually relieved with continued illumination. This study provides insights into how PET responds to a marked reduction in availability of downstream electron acceptors and the protective mechanisms involved.

We introduce ZNSwap , a novel swap subsystem optimized for the recent Zoned Namespace (ZNS) SSDs. ZNSwap leverages ZNS’s explicit control over data management on the drive and introduces a space-efficient host-side Garbage Collector (GC) for swap storage co-designed with the OS swap logic. ZNSwap enables cross-layer optimizations, such as direct access to the in-kernel swap usage statistics by the GC to enable fine-grain swap storage management, and correct accounting of the GC bandwidth usage in the OS resource isolation mechanisms to improve performance isolation in multi-tenant environments. We evaluate ZNSwap using standard Linux swap benchmarks and two production key-value stores. ZNSwap shows significant performance benefits over the Linux swap on traditional SSDs, such as stable throughput for different memory access patterns, and 10× lower 99th percentile latency and 5× higher throughput for memcached key-value store under realistic usage scenarios.

This article suggests a collection of model-based and model-free output-feedback optimal solutions to a general ${H_{∞}}$ control design criterion of a continuous-time linear system. The goal is to obtain a static output-feedback controller while the design criterion is formulated with an exponential term, divergent or convergent, depending on the designer's choice. Two offline policy-iteration algorithms are presented first, which form the foundations for a family of online off-policy designs. These algorithms cover all different cases of partial or complete model knowledge and provide the designer with a collection of design alternatives. It is shown that such a design for partial model knowledge can reduce the number of unknown matrices to be solved online. In particular, if the disturbance input matrix of the model is given, off-policy learning can be done with no disturbance excitation. This alternative is useful in situations where a measurable disturbance is not available in the learning phase. The utility of these design procedures is demonstrated for the case of an optimal lane tracking controller of an automated car.

Diffusing alpha-emitters Radiation Therapy (DaRT) releases alpha-emitting atoms into the tumor microenvironment. The treatment effectively ablates human and mice xenografts and shows 100% response rates in skin or head and neck squamous cell carcinoma patients. DaRT induces specific and systemic antitumor immune activation and synergizes with immune stimulation and modulation in mice. Here, the transcriptional profile activated by DaRT, and its potential to enhance responsiveness to immune checkpoint inhibition by programmed cell death protein 1 (PD-1) blockade were studied.Squamous cell carcinoma tumor- bearing BALB/C mice were treated with DaRT or inert seeds in combination with anti-PD-1 (aPD-1) or IgG control antibody. Sixteen days after seed insertion, tumors and spleens were subjected to immunophenotyping and immunohistochemical staining. Combination of DaRT and aPD-1 was tested for efficacy. Gene expression analysis was performed on mRNA extracted from tumors 7 days after DaRT or inert insertion using Nanostring PanCancer-IO-360 panel, and tumors and spleens were subjected to flow cytometry analysis.DaRT in combination with aPD-1 delayed tumor development, induced CD3 and CD8 lymphocytes infiltration more efficiently than either monotherapy. The combined treatment reduced splenic polymorphonuclear myeloid derived suppressor cells more than aPD-1 therapy or control. Granzyme B release in the tumor was increased only in the combinational treatment and was correlated with T-lymphocyte infiltration. Gene expression and gene set enrichment analysis of mRNA levels 7 days after DaRT insertion indicated that DaRT upregulated apoptosis, p53 signaling, G1/S-related arrest, interferon signaling and myeloid related transcription, while downregulating DNA repair, cell proliferation, and notch-related transcription. Flow cytometry showed that DaRT increased dendritic cells activation and led to changes in MDSCs distribution.DaRT promotes a "hot" tumor microenvironment and changes in immune suppression that lead to a potentiation of aPD-1 blockade induced effector T cell function and improved treatment efficacy. This study provides rationale for investigating DaRT and aPD-1 combination in patients with squamous cell carcinoma.

To identify risk factors associated with accidental fetal skin lacerations (AFL) during cesarean section (CS).This retrospective cohort study was obtained from the registry of two large medical centers between 2014 and 2019. The study group comprised all newborns identified with AFL. The rates of various potential risk factors were compared between the study group and a group of CS at which no AFL had occurred (the control group).Of the 14 666 CS deliveries, 48 cases of AFL (0.33%) were documented, 52% of these following urgent CS. Compared with the control group (n = 14 618), the only risk factors associated with AFL were premature rupture of membranes (PROM) (odds ratio [OR] 5.38, 95% convidence interval [CI] 2.97-9.74) and meconium-stained amniotic fluid (OR 6.50, 95% CI 2.55-16.54). In subgroup analysis by CS urgency, no significance for these factors was noted in elective CS group; but higher rates of both PROM and meconium-stained amniotic fluid were noted in the AFL during urgent CS (OR 14.23, 95% CI 6.30-32.16 and OR 15.36, (95% CI 5.65-41.75, respectively).During urgent CS, the surgeon should bear in mind that the presence of PROM or meconium-stained amniotic fluid should prompt extra care and application of preventive measures to decrease the rates of AFL.

In this research paper, authors provide a comprehensive overview and critique of the World System Analysis (also read as World System theory). This central focus is driven by the need to bring about a fair and justifiable explanation of the theory and appreciation by examining the work critically as the most persuasive theory in international relations. The aim of this paper is to bring about world system analysis as the best tool in analysing the world politics, understanding world history and key reasons for imperialism, and why core countries such as the United States of America (USA), China and etc., often intervene in world crises through grants and other forms of aid. The authors argue that the world system theory, unlike the dependency theory, is broader in perspective and place the world as a centre of attention in the analysis of the world economic distribution instead of the nation-state. Equally, it can also be deployed in understanding global inequality, dependency and power. The above argument which is achieved through the use of a qualitative approach that has taken the form of the adoption of secondary materials and the Afrocentric paradigm. In this research paper, authors provide a comprehensive overview and critique of the World System Analysis (also read as World System theory). This central focus is driven by the need to bring about a fair and justifiable explanation of the theory and appreciation by examining the work critically as the most persuasive theory in international relations. The aim of this paper is to bring about world system analysis as the best tool in analysing the world politics, understanding world history and key reasons for imperialism, and why core countries such as the United States of America (USA), China and etc., often intervene in world crises through grants and other forms of aid. The authors argue that the world system theory, unlike the dependency theory, is broader in perspective and place the world as a centre of attention in the analysis of the world economic distribution instead of the nation-state. Equally, it can also be deployed in understanding global inequality, dependency and power. The above argument which is achieved through the use of a qualitative approach that has taken the form of the adoption of secondary materials and the Afrocentric paradigm.

Molecular hydrogen adsorbed on graphene was investigated by analyzing rotational excitation spectra obtained with a gate-tunable scanning tunneling microscope (STM). Through the shift of the rotational excitation energy, the tunability of physisorbed H2 on graphene was evaluated in response to electric fields and surface charging. Since pristine graphene and molecular hydrogen are both inert in nature, direct observation of physisorbed H2 on graphene remains elusive as H2 binds too weakly to flat graphene, even at low temperatures. Here, molecular hydrogen was exposed to wrinkled graphene at 5 K. Localized charges in the wrinkled graphene stabilize the H2-graphene bonding and thus enable observation using gate-tunable STM. Gate biasing modifies the charge carrier density in graphene and the electric field applied to the system, allowing for control of the physisorption of H2 molecules on graphene. The interaction between the molecule and surface is altered significantly as the gate voltage changes from -40 to +40 V, which results in a shift of the J = 0 -> 2 rotational excitation of H2 from 47 to 53 meV. Our theoretical results show that the rotational energy barrier follows a parabolic function of the electric field whose maximum shifts with surface charge. This trend of electric field and charge dependence was experimentally observed by STM. Modulating the electric field and the amount of surface charging offers unique opportunities to control physisorbed molecules, which is reversible and nondestructive.

The use of three-dimensional (3-D) technology in upper extremity surgery has the potential to revolutionize the way that hand and upper limb procedures are planned and performed. 3-D technology can assist in the diagnosis and treatment of conditions, allowing virtual preoperative planning and surgical templating. 3-D printing can allow the production of patient-specific jigs, instruments and implants, allowing surgeons to plan and perform complex procedures with greater precision and accuracy. Previously, cost has been a barrier to the use of 3-D technology, which is now falling rapidly. This review article will discuss the current status of 3-D technology and printing, including its applications, ethics and challenges in hand and upper limb surgery. We have provided case examples to outline how clinicians can incorporate 3-D technology in their clinical practice for congenital deformities, management of acute fracture and malunion and arthroplasty.

The SCAPS-1D simulation tool was employed to conduct photoelectric simulation of perovskite solar cells in this paper. To begin with, a MAPbI3/MASnI3 layer was used as the perovskite absorption layer to investigate the performance of tandem perovskite solar cells. The influence of defect density and the work function of the front electrode on the device performance were studied. Additionally, the impact of temperature variations on device performance was studied. The results indicate that the MAPbI3/MASnI3 tandem perovskite solar cells achieve higher efficiency (30.05%) than the single-junction perovskite solar cells. Moreover, low defect density and temperature were found to be beneficial for higher performance. The heat distribution inside the device was studied using the finite element method. Furthermore, the influence of different hole transport materials and electron transport materials on the performance of perovskite solar cells with the hybrid perovskite layer (MAPbI3/MASnI3) was investigated and find out the appropriate transport layer materials. This research provides a reference for the perovskite solar cells.

Aims: To evaluate the role of nanoparticles (NP) in sputum samples of active smokers as markers of inflammation and disease. Materials & methods: 29 active smokers were included (14 with chronic obstructive pulmonary disease [COPD]) and underwent clinical assessment, pulmonary function tests, sputum induction (with NP analysis) and blood sampling. Results: Higher particle and NP concentrations and smaller mean size directly correlated with clinical parameters such as the COPD Assessment Test score and impulse oscillometry results. Similar correlations were found between NPs and increased sputum IL-1β, IL-6 and TNF-α. Among COPD patients, higher IL-8 and lower IL-10 serum levels also correlated with NP concentrations. Conclusion: This proof-of-concept study shows the potential of sputum NPs as markers of airway inflammation and disease.

Why do people often pursue social rank using coercive and potentially costly

The politics of knowledge in the world are as old as the cradle of human civilisation. The stakes of knowledge politics are higher in countries that have a rich history of colonialism, such as South Africa, Namibia and Zimbabwe, among others. In the post-apartheid South Africa, there has been a raging scholarly and policy debate about the dynamics of the knowledge industry within our shores. At the centre of this debate has been the role of statutory institutions, such as ASSAf, NRF, universities and research councils. Despite the expressed legislative framework, the role of these institutions in terms of knowledge generation and development has not been applied in line with this framework by their administrators. The policy makers have not yet seriously held them accountable. The consequence is that these administrators have been largely acting not within the national policy framework. In fact, this discourse has largely assumed the form of a conversation between the deaf. Drawing from the fusion of an alternative Afrocentric perspective and interdisciplinary discourse analysis in its broadest form, this paper argues that statutory institutions have an important national role to play in the knowledge industry. But their activities are not above board. If left operating the way they do, their wrong activities have a potential to undermine declared policy measures to the pursuit of true and quality knowledge.

Spatial modulation of electron beams is an essential tool for various applications such as nanolithography and imaging1–3 , yet its implementations4–11 are severely limited and inherently non-tunable. Conversely, light-driven electron spatial modulation12–15 could potentially allow arbitrary electron wavefront shaping16–18 via the underlying mechanism of photon-induced nearfield electron microscopy (PINEM)19–21 . Here, we present tunable photon-induced spatial modulation of electrons through their externally-controlled interaction with surface plasmon polaritons (SPPs). Using recently developed methods of shaping SPP patterns 22,23, we demonstrate a dynamic control of the electron beam with a variety of high-quality electron distributions. Intriguingly, by utilizing the intrinsic interaction nonlinearity24, we attain the first observation of 2D spatial Rabi oscillations25,26 and generate electron features below the SPP wavelength. Our work paves the way to on-demand electron wavefront shaping at ultrafast timescales, with prospects for aberration correction, nano-fabrication and material characterization., The results supporting the findings of this articles have received additional fundings from the Israel Science Foundation grants 3334/19 and 831/19

Both an improved understanding of acute myeloid leukemia (AML) pathophysiology plus improvements in measurement technology have led to revamping the diagnostic, prognostic, and therapeutic landscape of AML. New classification systems integrating molecular insights, updated risk assessment, improved ability to measure low levels of disease as well as least ten recently approved therapies may promote better outcomes including cures in a larger fraction of AML patients. The diagnostic and therapeutic complexity makes the decision-making process ever more individualized and requires integration of patient goals of care, comorbidities and disease characteristics including the specific mutational profile of the patient. In this review we present recent advances in diagnosis, classification, risk stratification and treatment options for patients with newly diagnosed (ND) or relapsed and refractory (R/R) AML. Such advances are welcome, but the increased options also lead to many controversies concerning the optimal selection of the timing and combinatorial use of the new drugs and how best to leverage our burgeoning ability to measure a small number of potentially malignant myeloid cells. In this context, we will present our approach for AML management noting current limitations and potential future directions. This article is protected by copyright. All rights reserved.

We summarize various effective methods for controlling the film thickness and structural phases in 2D/3D perovskite heterojunction structures and discuss possible solutions to improve the performance of perovskite devices.

Colorimetric sensing technology for the detection of explosives, drugs, and their precursor chemicals is an important and effective approach. In this work, we use various machine learning models to detect these substances from colorimetric sensing experiments conducted in controlled environments. The detection experiments based on the response of a colorimetric chip containing 26 chemo-responsive dyes indicate that homemade explosives (HMEs) such as hexamethylene triperoxide diamine (HMTD), triacetone triperoxide (TATP), and methyl ethyl ketone peroxide (MEKP) used in improvised explosives devices are detected with true positive rate (TPR) of 70–75%, 73–90% and 60–82% respectively. Time series classifiers such as Convolutional Neural Networks (CNN) are explored, and the results indicate that improvements can be achieved with the use of kinetics of the chemical responses. The use of CNNs is limited, however, to scenarios where a large number of measurements, typically in the range of a few hundred, of each analyte are available. Feature selection of important dyes using the Group Lasso (GPLASSO) algorithm indicated that certain dyes are more important in discrimination of an analyte from ambient air. This information could be used for optimizing the colorimetric sensor and extend the detection to more analytes.

Sarcopenia and sarcopenic obesity (SO) are linked to unfavorable prognosis in maintenance hemodialysis (MHD) populations. We tested whether nonobese sarcopenia and SO, as different stages of extreme protein-energy wasting, have different prognoses.In this prospective observational study, 261 MHD patients were recruited from October 2010 to April 2012 and followed until October 2020. Two definitions were used to diagnose sarcopenia: the European Working Group on Sarcopenia in Older People consensus and the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium criteria. Obesity was determined as the percentage of total body fat, ≥27% for men and ≥38% for women. Data for all-cause and cardiovascular morbidity and mortality, baseline nutrition markers, inflammation and oxidative stress, adipokines, body composition parameters, handgrip strength, and quality of life (QoL) scores were measured.According to European Working Group on Sarcopenia in Older People, 115 (44.1%) patients were sarcopenic and 120 (46.0%) according to FNIH definitions. Of them, 28.4% and 34.5% were SO, respectively. Higher levels of albumin, creatinine, uric acid, leptin, phase angle, better nutritional scores, and lower adiponectin levels characterized SO patients compared with nonobese sarcopenic patients regardless of indexing method. Better QoL scores were noted in SO compared with nonobese sarcopenic patients using the FNIH sarcopenia criteria. The hazard of all-cause death, cardiovascular death, and first cardiovascular event for patients with SO was lower compared with the nonobese patients after multivariate adjustments. Statistical significance of these associations disappeared after including fat mass in multivariate models.MHD patients with SO have better nutritional status and prognosis for cardiovascular events, all-cause and cardiovascular disease mortality, and possibly better QoL compared with nonobese sarcopenic MHD patients. The better prognosis appears to be entirely due to the excess fat, which is protective in sarcopenic MHD patients similar to that described in the entire MHD population.

A third dose of the BNT162b2 SARS-CoV-2 vaccine leads to a significant increase in antibody levels, however, concerns regarding the long-term persistence of this response exist. We assessed the humoral response for one year following vaccination.A prospective study among immunocompetent healthcare workers (HCW) who received three doses of BNT162b2. anti-spike antibody titers were measured at six predefined timepoints, from before the second vaccine dose, and up to one year afterwards, which is 4-6 months after the third dose. HCW with a history of SARS-CoV-2 infection were excluded.Seventy-six HCW had all the six serological measurements. Antibody titers significantly increased shortly following the third vaccine dose, and while declining, remained higher from all previous measurements for up to six months.A third dose of BNT162b2 leads to a profound humoral response, which remains significantly higher than previous measurements, even after 6 months.