Repurposing existing medications for coronavirus disease 2019: protocol for a rapid and living systematic review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has no confirmed specific treatments. However, there might be in vitro and early clinical data as well as evidence from severe acute respiratory syndrome and Middle Eastern respiratory syndrome that could inform clinicians and researchers. This systematic review aims to create priorities for future research of drugs repurposed for COVID-19. METHODS: This systematic review will include in vitro, animal, and clinical studies evaluating the efficacy of a list of 34 specific compounds and 4 groups of drugs identified in a previous scoping review. Studies will be identified both from traditional literature databases and pre-print servers. Outcomes assessed will include time to clinical improvement, time to viral clearance, mortality, length of hospital stay, and proportions transferred to the intensive care unit and intubated, respectively. We will use the GRADE methodology to assess the quality of the evidence. DISCUSSION: The challenge posed by COVID-19 requires not just a rapid review of drugs that can be repurposed but also a sustained effort to integrate new evidence into a living systematic review. TRIAL REGISTRATION: PROSPERO 2020 CRD42020175648.

Repurposing Existing Medications for Coronavirus Disease 2019: Protocol for a Rapid and Living Systematic Review.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) has no known specific treatments. However, there might be in vitro and early clinical data as well as evidence from Severe Acute Respiratory Syndrome and Middle Eastern Respiratory Syndrome that could inform clinicians and researchers. This systematic review aims to create priorities for future research of drugs repurposed for COVID-19. METHODS: This systematic review will include in vitro, animal, and clinical studies evaluating the efficacy of a list of 34 specific compounds and four groups of drugs identified in a previous scoping review. Studies will be identified both from traditional literature databases and pre-print servers. Outcomes assessed will include time to clinical improvement, time to viral clearance, mortality, length of hospital stay, and proportions transferred to the intensive care unit and intubated, respectively. We will use the GRADE methodology to assess the quality of the evidence. DISCUSSION: The challenge posed by COVID-19 requires not just a rapid review of drugs that can be repurposed but also a sustained effort to integrate new evidence into a living systematic review. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2020 CRD42020175648.

A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis.

Activating the intrinsic apoptosis pathway with small molecules is now a clinically validated approach to cancer therapy. In contrast, blocking apoptosis to prevent the death of healthy cells in disease settings has not been achieved. Caspases have been favored, but they act too late in apoptosis to provide long-term protection. The critical step in committing a cell to death is activation of BAK or BAX, pro-death BCL-2 proteins mediating mitochondrial damage. Apoptosis cannot proceed in their absence. Here we show that WEHI-9625, a novel tricyclic sulfone small molecule, binds to VDAC2 and promotes its ability to inhibit apoptosis driven by mouse BAK. In contrast to caspase inhibitors, WEHI-9625 blocks apoptosis before mitochondrial damage, preserving cellular function and long-term clonogenic potential. Our findings expand on the key role of VDAC2 in regulating apoptosis and demonstrate that blocking apoptosis at an early stage is both advantageous and pharmacologically tractable.

Gender Disparities in Invited Commentary Authorship in 2459 Medical Journals.

Importance: In peer-reviewed medical journals, authoring an invited commentary on an original article is a recognition of expertise. It has been documented that women author fewer invited publications than men do. However, it is unknown whether this disparity is due to gender differences in characteristics that are associated with invitations, such as field of expertise, seniority, and scientific output. Objective: To estimate the odds ratio (OR) of authoring an invited commentary for women compared with men who had similar expertise, seniority, and publication metrics. Design, Setting, and Participants: This matched case-control study included all medical invited commentaries published from January 1, 2013, through December 31, 2017, in English-language medical journals and multidisciplinary journals. Invited commentaries were defined as publications that cite another publication within the same journal volume and issue. Bibliometric data were obtained from Scopus. Cases were defined as corresponding authors of invited commentaries in a given journal during the study period. Controls were matched to cases based on scientific expertise by calculating a similarity index for abstracts published during the same period using natural language processing. Data analyses were conducted from March 13, 2019, through May 3, 2019. Exposure: Corresponding or sole author gender was predicted from author first name and country of origin using genderize.io. Main Outcomes and Measures: The OR for gender was estimated after adjusting for field of expertise, publication output, citation impact, and years active (ie, years since first publication), with an interaction between gender and years active. Results: The final data set included 43 235 cases across 2549 journals; there were 34 047 unique intraciting commentary authors, among whom 9072 (26.6%) were women. For researchers who had been active for the median of 19 years, the odds of invited commentary authorship were 21% lower for women (OR, 0.79 [95% CI, 0.77-0.81]; P < .001) compared with men who had similar scientific expertise, number of publications, and citation impact. For every decile increase in years active, the OR decreased by a factor of 0.97 (95% CI, 0.96-0.98; P < .001). Conclusions and Relevance: In this case-control study, women had lower odds of authoring invited commentaries than their male peers. This disparity was larger for senior researchers. Journal editors could use natural language processing of published research to widen and diversify the pool of experts considered for commentary invitations.

Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL.

Because of the promise of BCL-2 antagonists in combating chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), interest in additional selective antagonists of antiapoptotic proteins has grown. Beginning with a series of selective, potent BCL-XL antagonists containing an undesirable hydrazone functionality, in silico design and X-ray crystallography were utilized to develop alternative scaffolds that retained the selectivity and potency of the starting compounds.

Knowledge-based extraction of adverse drug events from biomedical text.

BACKGROUND: Many biomedical relation extraction systems are machine-learning based and have to be trained on large annotated corpora that are expensive and cumbersome to construct. We developed a knowledge-based relation extraction system that requires minimal training data, and applied the system for the extraction of adverse drug events from biomedical text. The system consists of a concept recognition module that identifies drugs and adverse effects in sentences, and a knowledge-base module that establishes whether a relation exists between the recognized concepts. The knowledge base was filled with information from the Unified Medical Language System. The performance of the system was evaluated on the ADE corpus, consisting of 1644 abstracts with manually annotated adverse drug events. Fifty abstracts were used for training, the remaining abstracts were used for testing. RESULTS: The knowledge-based system obtained an F-score of 50.5%, which was 34.4 percentage points better than the co-occurrence baseline. Increasing the training set to 400 abstracts improved the F-score to 54.3%. When the system was compared with a machine-learning system, jSRE, on a subset of the sentences in the ADE corpus, our knowledge-based system achieved an F-score that is 7 percentage points higher than the F-score of jSRE trained on 50 abstracts, and still 2 percentage points higher than jSRE trained on 90% of the corpus. CONCLUSION: A knowledge-based approach can be successfully used to extract adverse drug events from biomedical text without need for a large training set. Whether use of a knowledge base is equally advantageous for other biomedical relation-extraction tasks remains to be investigated.

The evaluation of solution- and solid-phase approaches to the divergent synthesis cinnoline and phenanthrene ring systems: SCS-09 special issue-combinatorial approaches to discovery.

Cinnoline and phenanthrene ring systems have been synthesized from a set of readily available substrates using functional group tolerant reactions. This approach proved successful in both solution- and solid-phase synthesis for phenanthrenes but was limited to solution-phase synthesis for cinnolines. The described approaches to these ring systems complements related approaches to other scaffolds that can be readily accessed from the same substrates using slight variations in the applied chemistry.

Solid-phase synthesis of 2,3-disubstituted benzo[b]thiophenes and benzo[b]selenophenes.

A concise and efficient solid-phase synthesis of benzo[b]thiophenes and benzo[b]selenophenes based on a combination of palladium-mediated coupling and iodocyclization protocols has been developed.

UV-visible spectral identification of the solution-phase and solid-phase permanganate oxidation reactions of thymine acetic acid.

Solution-phase and solid-phase permanganate oxidation reactions of thymine acetic acid were investigated by spectroscopy. The spectral data showed the formation of a stable organomanganese intermediate, which was responsible for the rise in the absorbance at 420 nm. This result enables unambiguous interpretation of the absorbance change at 420 nm, as the intermediate permanganate ions could be isolated on the solid supports.

Spectroscopic study of permanganate oxidation reactions of oligonucleotides containing single base mismatches.

The electrophoretic gel-based chemical cleavage of the mismatch method gives an incomplete view of the DNA conformational changes induced by a single base mismatch. This spectroscopic study investigates the permanganate oxidation reactions with matched and mismatched DNA under constant and variable temperature conditions. The results, which include the oxidation levels, reaction patterns with isosbestic points, color changes, thermal spectra, spectroscopy derivative, and gel separation and melting temperatures, provide a fundamental background for identification of oligonucleotides containing single base mismatches by chemical means.

Permanganate oxidation reactions of DNA: perspective in biological studies.

KMnO4 has been well known as a powerful chemical probe for numerous applications in biological fields, particularly for those used in conformational studies of DNA. The KMnO4 assay provides essential information for understanding biochemical processes and detecting aberrant DNA, which is associated with many genetic diseases. Elegant examples are sequencing techniques, foot-printing assays for transcriptional studies, an interference method for hormone receptor binding assays as well as DNA conformational studies of Z-DNA, Z-Z junctions, hairpins, curvatures, short nucleotide base repeats, binding of intercalators and groove binders, etc. Recently, KMnO4 has been successfully applied to detect single base changes and mutations in DNA (chemical cleavage of mismatch method, CCM) as well as other types of base damage (8-oxoguanine and thymine dimers). This paper aims to review the usefulness and limitations of the permanganate oxidation reaction used in various biological studies of DNA.

Chemical cleavage reactions of DNA on solid support: application in mutation detection.

BACKGROUND: The conventional solution-phase Chemical Cleavage of Mismatch (CCM) method is time-consuming, as the protocol requires purification of DNA after each reaction step. This paper describes a new version of CCM to overcome this problem by immobilizing DNA on silica solid supports. RESULTS: DNA test samples were loaded on to silica beads and the DNA bound to the solid supports underwent chemical modification reactions with KMnO4 (potassium permanganate) and hydroxylamine in 3M TEAC (tetraethylammonium chloride) solution. The resulting modified DNA was then simultaneously cleaved by piperidine and removed from the solid supports to afford DNA fragments without the requirement of DNA purification between reaction steps. CONCLUSIONS: The new solid-phase version of CCM is a fast, cost-effective and sensitive method for detection of mismatches and mutations.

Site-selective reactions of imperfectly matched DNA with small chemical molecules: applications in mutation detection.

The last decade has witnessed many exciting scientific publications associated with site-selective reactions of small chemical molecules with imperfectly matched DNA. Typical examples are carbodiimide, hydroxylamine, potassium permanganate, osmium tetroxide, chemical tagging probes, biotinylated, chemiluminescent and fluorescent probes, and all of them selectively react with imperfectly matched DNA. More recently, some therapeutic agents including DNA intercalating drugs and groove binders have been found to promote the in vivo repair system to recognize and repair the mismatch more effectively. The results have established a novel method for detection of mismatches. Development of new chemical reactions for detection of imperfectly matched DNA and mutations is a rapidly growing field and has attracted significant interest of scientists from both chemical and biological fields and it is the main focus of this review.

Comparative study of permanganate oxidation reactions of nucleotide bases by spectroscopy.

The permanganate oxidation of free nucleotide bases was successfully studied in aqueous solution of tetraethylammonium chloride using spectroscopic techniques. The reaction was highly selective toward thymine and uracil, less with cytosine, very little reaction on guanine, and no reaction on adenine.