The coronavirus disease 2019 (COVID-19) virus is spreading rapidly, and scientists are endeavoring to discover drugs for its efficacious treatment in China. Chloroquine phosphate, an old drug for ...treatment of malaria, is shown to have apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multicenter clinical trials conducted in China. The drug is recommended to be included in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People's Republic of China for treatment of COVID-19 infection in larger populations in the future.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The SARS-CoV-2 virus emerged in December 2019 and then spread rapidly worldwide, particularly to China, Japan, and South Korea. Scientists are endeavoring to find antivirals specific to the virus. ...Several drugs such as chloroquine, arbidol, remdesivir, and favipiravir are currently undergoing clinical studies to test their efficacy and safety in the treatment of coronavirus disease 2019 (COVID-19) in China; some promising results have been achieved thus far. This article summarizes agents with potential efficacy against SARS-CoV-2.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This article examines the practice of the international judicial and arbitral tribunals thus far in delimiting the continental shelf beyond 200 nm, and indicates the trend reflected in the decisions. ...However, the article disagrees with the critical observation of the tribunals that the delimitation method for the continental shelf beyond 200 nm should follow that within 200 nm. The delimitation of the continental shelf beyond 200 nm is essentially different from the single maritime delimitation within 200 nm, and various methods may be employed in order to achieve an equitable result in a particular case.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, PRFLJ, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Accurate modeling and efficient parameter extraction of the equivalent circuit model of high-speed vertical-cavity surface emitting lasers (VCSELs) for high-frequency operation based on the rate ...equations are presented in this paper. The model is versatile in that it permits dc, small signal, and large signal to be performed, and can be easily on commercial circuit software. An analytical method, along with closed-form solution, to determine parasitic elements, intrinsic model parameters and rate equation model parameters of the VCSELs is developed and experimentally verified using on wafer measurement of electronic and optical performance. Modeled and measured results for the input reflection coefficients and modulation responses exhibit good agreement over a wide range of bias points under cutoff and above-threshold biased condition in the frequency range of 50 MHz-20 GHz for an oxide-confined AlGaAs VCSELs.
Drugs that are specifically efficacious against SARS-CoV-2 have yet to be established. Chloroquine and hydroxychloroquine have garnered considerable attention for their potential to treat coronavirus ...disease 2019 (COVID-19). Increasing evidence obtained from completed clinical studies indicates the prospects for chloroquine/hydroxychloroquine to treat COVID-19. More randomized control clinical studies are warranted to determine the feasibility of these two drugs in treating COVID-19.
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Immune checkpoint therapy (ICT) can provide durable clinical responses and improve overall survival. However, only subsets of patients with specific tumor types respond to ICT. Thus, significant ...challenges remain, including understanding pathways of resistance, optimizing patient selection, improving management of immune-related adverse events, and identifying rational therapeutic combinations. These challenges will need a focused approach encompassing both clinical and basic research, with the integration of reverse translational studies. This integrated approach will lead to identification of potential targets for subsequent clinical trials, which will guide decisions as we develop novel combination strategies to maximize efficacy and minimize toxicities for patients. SIGNIFICANCE: ICTs induce durable antitumor responses for subsets of patients with cancer. Recent evidence suggests that rational combinatorial strategies can improve response by overcoming primary and adaptive resistance mechanisms, although these may carry an increased risk of immune-mediated toxicities. This review surveys the current understanding of mechanisms of response and resistance to ICTs and active areas of investigation, and proposes a path forward to improving efficacy and minimizing toxicities through better patient selection and rational combinations.
Accumulating evidence indicates that patient-derived organoids (PDOs) can predict drug responses in the clinic, but the ability of PDOs to predict responses to chemoradiation in cancer patients ...remains an open question. Here we generate a living organoid biobank from patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation (NACR) enrolled in a phase III clinical trial. Our co-clinical trial data confirm that rectal cancer organoids (RCOs) closely recapitulate the pathophysiology and genetic changes of corresponding tumors. Chemoradiation responses in patients are highly matched to RCO responses, with 84.43% accuracy, 78.01% sensitivity, and 91.97% specificity. These data imply that PDOs predict LARC patient responses in the clinic and may represent a companion diagnostic tool in rectal cancer treatment.
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•Living biobank with 80 tumor organoids was derived from treatment-naive CRC patients•Tumor organoids recapitulate histological and genetic features of original tumors•Interpatient variability in the PDO response to chemoradiation treatments•PDOs can predict locally advanced rectal cancer patient responses in the clinic
Yao et al. generated a patient-derived organoid (PDO) biobank from patients with locally advanced rectal cancer (LARC) and reported that organoids had similar molecular profiles to those of the patient tumor and that PDOs can predict LARC patient chemoradiation responses, reinforcing their value as a companion diagnostic tool in LARC treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary ...resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in ~13% of all cancers. We demonstrate that 9p21 loss confers "cold" tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A "response score" was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions.
One long-standing challenge in both the optimization and investment communities is to devise an efficient algorithm to select a small number of assets from an asset pool such that a portfolio ...objective is optimized. This cardinality constrained investment situation naturally arises due to the presence of various forms of market friction, such as transaction costs and management fees, or even due to the consideration of mental cost. Unfortunately, the combinatorial nature of such a portfolio selection problem formulation makes the exact solution process NP-hard in general. We focus in this paper on the cardinality constrained mean-variance portfolio selection problem. Instead of tailoring such a difficult problem into the general solution framework of mixed-integer programming formulation, we explore the special structures and rich geometric properties behind the mathematical formulation. Applying the Lagrangian relaxation to the primal problem results in a pure cardinality constrained portfolio selection problem, which possesses a symmetric property, and to which geometric approaches can be developed. Different from the existing literature that has primarily focused on some direct relaxations of the cardinality constraint, we consider modifying the objective function to some separable relaxations, which are immune to the hard cardinality constraint. More specifically, we develop efficient lower bounding schemes by using the circumscribed box, the circumscribed ball, and the circumscribed axis-aligned ellipsoid to approximate the objective contour of the problem. In particular, all these cardinality constrained relaxation problems can be solved analytically. Furthermore, we derive efficient polynomial-time algorithms for the corresponding dual search problems. Most promisingly, the lower bounding scheme using the circumscribed axis-aligned ellipsoid leads to a semidefinite programming (SDP) formulation and offers a sharp bound and high-quality feasible solution. By integrating these lower bounding schemes into a branch-and-bound algorithm (BnB), our solution scheme outperforms CPLEX significantly in identifying the exact optimal portfolio.
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BFBNIB, CEKLJ, IZUM, KILJ, NMLJ, NUK, ODKLJ, PILJ, PNG, SAZU, UL, UM, UPUK
The Timor Sea Conciliation is the first experience with the compulsory conciliation under Annex V of the 1982 United Nations Convention on the Law of the Sea. The Conciliation Commission addressed ...the objections to its competence as a preliminary matter and rendered a separate decision. This article examines the approach of the Conciliation Commission in dealing with its competence issues and the understandings of the Conciliation Commission as regards the relevant provisions of the 1982 Convention.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, PRFLJ, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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