Difficult at dusk? Illuminating the debate on cricket ball visibility.

OBJECTIVES: Investigate the visibility of new and old red, white and pink cricket balls under lighting and background conditions experienced during a day-night cricket match. DESIGN: We modelled the luminance contrast signals available for a typical observer for a ball against backgrounds in a professional cricket ground, at different times of day. METHODS: Spectral reflectance (light reflected as a function of wavelength) was derived from laboratory measurements of new and old red, white and pink balls. We also gathered spectral measurements from backgrounds (pitch, grass, sightscreens, crowd, sky) and spectral illuminance during a day-night match (natural afternoon light, through dusk to night under floodlights) from Lord's Cricket Ground (London, UK). The luminance contrast of the ball relative to the background was calculated for each combination of ball, time of day, and background surface. RESULTS: Old red and old pink balls may offer little or no contrast against the grass, pitch and crowd. New pink balls can also be of low contrast against the crowd at dusk, as can pink and white balls (of any age) against the sky at dusk. CONCLUSIONS: Reports of difficulties with visibility of the pink ball are supported by our data. However, our modelling also shows that difficulties with visibility may also be expected under certain circumstances for red and white balls. The variable conditions in a cricket ground and the changing colour of an ageing ball make maintaining good visibility of the ball a challenge when playing day-night matches.

Correction to 'Tumor-selective, antigen-independent delivery of a pH sensitive peptide-topoisomerase inhibitor conjugate suppresses tumor growth without systemic toxicity'.

[This corrects the article DOI: 10.1093/narcan/zcab021.].

Tumor-selective, antigen-independent delivery of a pH sensitive peptide-topoisomerase inhibitor conjugate suppresses tumor growth without systemic toxicity.

Topoisomerase inhibitors are potent DNA damaging agents which are widely used in oncology, and they demonstrate robust synergistic tumor cell killing in combination with DNA repair inhibitors, including poly(ADP)-ribose polymerase (PARP) inhibitors. However, their use has been severely limited by the inability to achieve a favorable therapeutic index due to severe systemic toxicities. Antibody-drug conjugates address this issue via antigen-dependent targeting and delivery of their payloads, but this approach requires specific antigens and yet still suffers from off-target toxicities. There is a high unmet need for a more universal tumor targeting technology to broaden the application of cytotoxic payloads. Acidification of the extracellular milieu arises from metabolic adaptions associated with the Warburg effect in cancer. Here we report the development of a pH-sensitive peptide-drug conjugate to deliver the topoisomerase inhibitor, exatecan, selectively to tumors in an antigen-independent manner. Using this approach, we demonstrate potent in vivo cytotoxicity, complete suppression of tumor growth across multiple human tumor models, and synergistic interactions with a PARP inhibitor. These data highlight the identification of a peptide-topoisomerase inhibitor conjugate for cancer therapy that provides a high therapeutic index, and is applicable to all types of human solid tumors in an antigen-independent manner.

Is the pink ball still under review? Cricket umpires' perceptions of the pink ball for day/night matches.

OBJECTIVES: The visibility of the pink ball used in day/night Test cricket has been under scrutiny, with recent research suggesting cricketers find the pink ball less visible at dusk under floodlights. With increasing interest in this match format, this study sought to investigate elite umpires' opinions pertaining to the visibility of the pink cricket ball during day/night matches. DESIGN: Purposeful sampling of a cross-section of elite umpires with experience adjudicating matches played using a pink cricket ball. METHODS: Twenty-seven international/first-class umpires completed a questionnaire consisting of Likert scale and free text responses covering perceptions of the pink cricket ball, with a particular emphasis on visibility. RESULTS: The pink ball when viewed at night under floodlights was rated as being significantly more visible than the red ball during natural lighting (ps<0.050). Umpires who actively participated in training reported a significantly higher rating of the visibility of the pink ball (mean -3.14) at night under floodlights compared to those who didn't (mean p=0.010). No significant difference was reported in visibility in natural light or dusk under floodlights. Free text responses (n=10) revealed the following themes: use of eyewear (coverage 0.30), and adjustment to positioning (coverage 0.20) to improve visibility of the pink ball. CONCLUSIONS: Umpires report the visibility of the pink ball is equal to the red in natural light and at dusk but is significantly better at night. Preference for the pink ball is likely due to the predominantly perceptual nature of visual tasks performed by umpires.

Cricketers are not tickled pink by the new coloured ball.

OBJECTIVES: Cricket administrators have started scheduling long-form matches which finish at night and are played with a pink as opposed to a red ball. However, there are reports that the pink ball may introduce new dangers and alter performance. The aim of this study was to investigate professional cricketers' opinions about the visibility of the pink ball whilst playing in different lighting conditions (afternoon, dusk and night). DESIGN: Purposeful sampling of a cross-section of elite cricketers with pink ball experiences playing in the United Kingdom. METHODS: Eighty-eight international or first-class professional cricketers completed a questionnaire consisting of Likert scale and free text responses to questions covering perceptions of the pink ball, with a particular emphasis on visibility. RESULTS: The pink ball was reported as less visible than the red ball when batting (p<0.001) and fielding (p<0.001). Within the three lighting conditions the pink ball was significantly less visible at dusk under floodlights compared to afternoon and night both when batting and fielding (ps<0.001). Free text comments confirmed that visibility of the pink cricket ball was most challenging at dusk (coverage 0.37), and that players sometimes experienced a blurring sensation with the pink ball leaving a visual 'trail' when viewed under floodlights (coverage 0.24). CONCLUSIONS: Results advocate that governing bodies should consider the inclusion of a break in play during dusk to enhance player safety and performance. Empirical research is needed to quantify the risks to player safety in different lighting conditions.

Stereoelectronic Effects in Ligand Design: Enantioselective Rhodium-Catalyzed Hydrogenation of Aliphatic Cyclic Tetrasubstituted Enamides and Concise Synthesis of (R)-Tofacitinib.

We herein report the development of a conformationally defined, electron-rich, C2 -symmetric, P-chiral bisphosphorus ligand, ArcPhos, by taking advantage of stereoelectronic effects in ligand design. With the Rh-ArcPhos catalyst, excellent enantioselectivities and unprecedentedly high turnovers (TON up to 10 000) were achieved in the asymmetric hydrogenation of aliphatic carbocyclic and heterocyclic tetrasubstituted enamides, to generate a series of chiral cis-2-alkyl-substituted carbocyclic and heterocyclic amine derivatives in excellent enantiomeric ratios. This method also enabled an efficient and practical synthesis of the Janus kinase inhibitor (R)-tofacitinib.

Pyrimidone-based series of glucokinase activators with alternative donor-acceptor motif.

Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.

Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors.

Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.

C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization.

Modifications to the sugar portion of C-aryl glycoside sodium glucose transporter 2 (SGLT2) inhibitors were explored, including systematic deletion and modification of each of the glycoside hydroxyl groups. Based on results showing activity to be quite tolerant of structural change at the C-5 position, a series of novel C-5 spiro analogues was prepared. Some of these analogues exhibit low nanomolar potency versus SGLT2 and promote urinary glucose excretion (UGE) in rats. However, due to sub-optimal pharmacokinetic parameters (in particular half-life), predicted human doses did not meet criteria for further advancement.

Oxygenated analogues of UK-396082 as inhibitors of activated thrombin activatable fibrinolysis inhibitor.

A suitable inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa) has the potential to be a novel treatment for thrombosis. The TAFIa inhibitor UK-396082 (1) was used as a starting point to seek more potent analogues. With knowledge of encouraging human pharmacokinetics and toleration for the clinical candidate (1), the programme continued to seek structure-activity relationships (SAR) that could positively impact on both potency and half-life, and therefore the projected dose of any future nominated clinical agent. A series of oxygenated analogues based on compound 1 were prepared to evaluate changes in pharmacology, selectivity and pharmacokinetics.

1,4-Asymmetric Induction in the Chromium(II)- and Indium-Mediated Coupling of Allyl Bromides to Aldehydes.

A series of allyl bromides bearing an ethereal stereogenic substituent at C-2 were synthesized from methyl acrylate. These were coupled with a range of aldehydes under chromium(II) chloride-mediated conditions to afford syn-4-alkoxyalkan-1-ols in good yield and diastereoselectivity. The effect of altering the nature of the ethereal group and alkyl substituent upon the diastereoselectivity of the reaction was also investigated. The relative stereochemistry was proved by X-ray structure analysis. The work was extended to replace the chromium(II) chloride with indium metal, and this also afforded syn-4-alkoxyalkan-1-ols in good yield and diastereoselectivity.