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Pyrrolobenzodiazepine (PBD) dimers are well-known highly potent antibody drug conjugate (ADC) payloads. The corresponding PBD monomers, in contrast, have received much less attention from the ADC community. We prepared several novel polyamide-linked PBD monomers and evaluated their utility as ADC payloads. The unconjugated polyamide-PBD hybrids exhibited potent antiproliferative activity (IC50 range: 10

Background/Aims Population-based studies suggest an association between pain in elderly adults and cognitive impairment. However, the temporal relationship between chronic pain and cognitive decline is uncertain: most studies are cross-sectional or have short follow-up periods. Our aim was to examine the association between two pain phenotypes - bodily pain and multi-joint pain - in middle-life and cognitive impairment in later-life in a prospective cohort study with 23 years’ follow-up. We also set out to examine the association with mortality. In contrast to much previous work, this study has available a comprehensive depth of information on health and pain characteristics over a long follow-up period. Methods Bodily pain and multi-joint pain at 3 timepoints between baseline and year 10 was measured in participants from the Chingford Women’s Study. Secondary analyses were performed on the two dimensions of bodily pain, pain intensity and interference. Multivariable logistic regression analysis was used to assess the association with cognition at year 23: the primary cognitive outcome was Mini-Mental State Examination (MMSE) score ≤28, with a secondary outcome of ≤ 26. Multivariable Cox regression analysis was used to evaluate the association between each pain exposure and all-cause mortality between years 10 and 23. Analyses were adjusted for education, socio-demographic factors, and modifiable risk factors for cognitive impairment including depression and analgesia use. Results 282 (28.1%) and 276 (27.5%) women were included in analyses for cognition and bodily pain and multi-joint pain respectively. Women with severe bodily pain showed a non-significant greater odds of MMSE ≤28 compared to those with no/mild bodily pain (OR 2.56, 95%CI 0.94-6.95, P = 0.07). Those with severe bodily pain had significantly greater odds of MMSE ≤26 (OR 7.31, 95%CI 2.11-25.36, P = 0.002). However, there was no association with multi-joint pain. Secondary analysis of the two dimensions of bodily pain demonstrated that pain interference displayed a stronger relationship with both MMSE thresholds compared to pain intensity. Women with severe bodily pain and repeated multi-joint pain each had higher crude all-cause mortality, but this was not statistically significant (log-rank test for trend, P = 0.11 & 0.068, respectively). Further adjustment left the association with both pain exposures and all-cause mortality entirely attenuated. Conclusion After 13 years’ follow-up, severe bodily pain but not multi-joint pain in mid-life was associated with subsequent cognitive impairment, determined by MMSE ≤26. Women with severe bodily pain and multi-joint pain had higher crude all-cause mortality rate, but this was not statistically significant after adjustment. Pain interference displayed a stronger association with cognitive impairment; this may reflect the impact of pain on functional status. This study represents the first time the consequences of mid-life pain on later life cognition were examined. Chronic pain, which is largely untreated, may thus represent a modifiable cause of cognitive impairment. Disclosure E. Kelleher: None. S. Hawley: None. A. Delmestri: None. N. Arden: None. I. Tracey: None. A. Soni: None.

Chronic kidney disease (CKD) is strongly associated with the full spectrum of cerebrovascular disease including ischaemic and haemorrhagic stroke, small vessel disease, and vascular cognitive impairment. Shared conventional vascular risk factors such as age, hypertension, and diabetes mellitus may account for many of these associations, but novel renal-specific risk factors such as uraemia-related coagulopathy or endothelial dysfunction have also been proposed. In this chapter, we will explore the impact of CKD on stroke risk, mechanisms, and outcomes. We will also outline potential challenges and inequities in stroke care delivery and research for these patients along with some strategies to help improve stroke prevention and management for this high-risk group.

STING pathway agonism has emerged as a potential therapeutic strategy to stimulate anti-tumor immune responses. We have previously shown that tumor cell-targeted antibody-drug conjugates (ADCs) carrying a novel STING agonist induce anti-tumor activity without causing substantial elevations in systemic cytokine levels, thus suggesting a therapeutic advantage of STING agonist ADCs relative to unconjugated agonists. ADCs constitute a proven therapeutic modality that is ideally suited to enable systemic administration and delivery of the conjugated drug to desired cell types within the tumor microenvironment. In addition to delivering STING agonist into the antigen-expressing tumor cells, antigen-bound ADCs deliver STING agonist to tumor-resident myeloid cells through Fcγ receptor (FcγR)-mediated internalization. In this study we investigated the mechanism of FcγR-mediated internalization of the tumor cell-targeted STING-agonist ADCs into myeloid cells and the nature of the subsequent STING pathway activation. We developed flow cytometry-based assays to determine the changes in FcγRI, FcγRII, and FcγRIII cell surface detection levels in the presence of ADCs specifically designed to be either proficient or deficient in FcγR-binding. Combined with functional assays based on co-culture of cancer cells and FcγRI knock out myeloid cells, we identified FcγRI as the major Fcγ receptor that mediates target-bound ADC internalization into myeloid cells in vitro. Even though FcγRI is expressed only by a subset of CD11b+ myeloid cells, tumor cell-targeted ADCs induce greater production of interferons and other cytokines and more potent cancer cell killing than CD11b-targeted-ADCs, which deliver STING agonist into FcγRI- (non-productive) as well as FcγRI+ (productive) myeloid cells. Finally, we demonstrate that myeloid cells within dissociated primary human tumors from multiple donors express FcγRI and are capable of tumor cell killing in response to tumor cell-targeted STING agonist ADCs in vitro. In summary, our data indicate that the ADC-mediated delivery of a STING agonist specifically into FcγRI-expressing myeloid cells efficiently activates innate immune responses in the most relevant immune cell types within the tumor microenvironment. Citation Format: Naniye Malli Cetinbas, Kalli C. Catcott, Travis Monnell, Jahna Soomer-James, Keith Bentley, Susan Clardy, Bingfan Du, Eoin Kelleher, Marina Protopopova, Cheri Stevenson, Joshua D. Thomas, Alex Uttard, Dorin Toader, Jeremy Duvall, Raghida Bukhalid, Marc Damelin, Timothy B. Lowinger. Tumor cell-targeted STING-agonist antibody-drug conjugates achieve potent anti-tumor activity by delivering STING agonist specifically to tumor cells andFcγRI-expressing subset of myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2114.

BACKGROUND Early evidence of COVID-19–associated coagulopathy disseminated rapidly online during the first months of 2020, followed by clinical debate about how best to manage thrombotic risks in these patients. The rapid online spread of case reports was followed by online interim guidelines, discussions, and worldwide online searches for further information. The impact of global online search trends and online discussion on local approaches to coagulopathy in patients with COVID-19 has not been studied. OBJECTIVE The goal of this study was to investigate the relationship between online search trends using Google Trends and the rate of appropriate venous thromboembolism (VTE) prophylaxis and anticoagulation therapy in a cohort of patients with COVID-19 admitted to a tertiary hospital in Ireland. METHODS A retrospective audit of anticoagulation therapy and VTE prophylaxis among patients with COVID-19 who were admitted to a tertiary hospital was conducted between February 29 and May 31, 2020. Worldwide Google search trends of the term “COVID-19” and anticoagulation synonyms during this time period were determined and correlated against one another using a Spearman correlation. A P value of RESULTS A statistically significant Spearman correlation (Pr=0.71) was found between the two data sets, showing an increase in VTE prophylaxis in patients with COVID-19 with increasing online searches worldwide. This represents a proxy for online searches and discussion, dissemination of information, and Google search trends relating to COVID-19 and clotting risk, in particular, which correlated with an increasing trend of providing thromboprophylaxis and anticoagulation therapy to patients with COVID-19 in our tertiary center. CONCLUSIONS We described a correlation of local change in clinical practice with worldwide online dialogue and digital search trends that influenced individual clinicians, prior to the publication of formal guidelines or a local quality-improvement intervention.

Background Early evidence of COVID-19–associated coagulopathy disseminated rapidly online during the first months of 2020, followed by clinical debate about how best to manage thrombotic risks in these patients. The rapid online spread of case reports was followed by online interim guidelines, discussions, and worldwide online searches for further information. The impact of global online search trends and online discussion on local approaches to coagulopathy in patients with COVID-19 has not been studied. Objective The goal of this study was to investigate the relationship between online search trends using Google Trends and the rate of appropriate venous thromboembolism (VTE) prophylaxis and anticoagulation therapy in a cohort of patients with COVID-19 admitted to a tertiary hospital in Ireland. Methods A retrospective audit of anticoagulation therapy and VTE prophylaxis among patients with COVID-19 who were admitted to a tertiary hospital was conducted between February 29 and May 31, 2020. Worldwide Google search trends of the term “COVID-19” and anticoagulation synonyms during this time period were determined and correlated against one another using a Spearman correlation. A P value of Results A statistically significant Spearman correlation (P Conclusions We described a correlation of local change in clinical practice with worldwide online dialogue and digital search trends that influenced individual clinicians, prior to the publication of formal guidelines or a local quality-improvement intervention.

STING pathway plays a critical role in inducing anti-tumor immunity by upregulating Type 1 Interferon (IFN) and IFN-stimulated genes within the tumor microenvironment in response to cytosolic nucleic acid ligands. Therefore, the STING pathway agonism has emerged as a potential therapeutic mechanism to stimulate an anti-tumor innate immune response. Intratumorally injected free STING-agonists that are currently being evaluated in the clinic by others have shown limited effects in non-injected lesions. Antibody-drug conjugates (ADCs) constitute a proven therapeutic modality that enables tumor-targeted drug delivery with systemic administration. We have previously demonstrated that the tumor cell-intrinsic STING pathway is activated in the presence of cues from immune cells and contributes to the anti-tumor activity of tumor cell-targeted Immunosynthen STING-agonist ADCs, in which a STING-agonist payload is conjugated to a tumor cell-targeting antibody. Here we investigated the nature of the STING pathway activation in tumor cells and its contribution to the anti-tumor activity elicited by STING agonism. Leveraging ADCs with a wild type (wt) or mutant Fc (deficient in Fcγ receptor -FcγR- binding), we delivered a STING-agonist simultaneously to tumor-resident immune and cancer cells or only to cancer cells through FcγR-mediated and/or tumor antigen-mediated ADC internalization. We utilized these ADCs in in vivo human tumor xenograft models and STING wt or knock out (ko) cancer cell:immune cell co-cultures and evaluated gene expression, cytokine production, and anti-tumor activities induced by STING-agonist ADCs. Surprisingly, Nanostring analysis of the human tumor xenografts from mice treated with tumor cell-targeted STING-agonist ADCs revealed human tumor cell-specific activation of Type III IFNs. In human cancer cell:immune cell co-cultures, treatment with tumor cell-targeted STING-agonist ADCs also led to marked upregulation of Type III IFNs, which was significantly reduced in STING ko cancer cell:immune cell co-cultures, suggesting that the cancer cells may contribute majority of the Type III IFNs downstream of STING pathway activation. Blocking Type III IFNs with neutralizing antibodies in cancer cell:immune cell co-cultures inhibited the production of key cytokines, including Type I IFN, and nearly abolished tumor cell-killing in response to STING-agonist ADC treatment, indicating that the Type III IFNs play an important role in the anti-tumor activity induced by STING activation. These studies reveal a previously underappreciated mechanism of STING agonist anti-tumor activity. The ability of tumor cell-targeted STING-agonist ADCs to activate STING in both tumor cells and in tumor-resident immune cells may represent a significant therapeutic advantage of an Immunosynthen ADC approach to STING agonism. Citation Format: Naniye Malli Cetinbas, Travis Monnell, Kalli Catcott, Winnie Lee, Pamela Shaw, Kelly Slocum, Kenneth Avocetien, Keith Bentley, Susan Clardy, Brian Jones, Eoin Kelleher, Rebecca Mosher, Joshua D. Thomas, Dorin Toader, Jeremy Duvall, Raghida A. Bukhalid, Marc Damelin, Timothy B. Lowinger. Tumor cell-intrinsic STING pathway activation leads to robust induction of Type III Interferons and contributes to the anti-tumor activity elicited by STING agonism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1773.

In recent years, three-dimensional printing has demonstrated reliable reproducibility of several organs including hearts with complex congenital cardiac anomalies. This represents the next step in advanced image processing and can be used to plan surgical repair. In this study, we describe three children with complex univentricular hearts and abnormal systemic or pulmonary venous drainage, in whom three-dimensional printed models based on CT data assisted with preoperative planning. For two children, after group discussion and examination of the models, a decision was made not to proceed with surgery. We extend the current clinical experience with three-dimensional printed modelling and discuss the benefits of such models in the setting of managing complex surgical problems in children with univentricular circulation and abnormal systemic or pulmonary venous drainage.

The brain is our most important organ and perhaps the least well understood. Our brain is the “command station” for our body. It controls what we think, what we feel and what we do. It is the home of our emotions and personality. It makes sense of our experiences. But how does the brain work? The truth is that, after decades of research, scientists and doctors are only now beginning to figure out that question. We know that different types of cells in the brain work together to form certain areas which have specialist roles in memory, vision and logical thinking. We also know that hormones and chemicals influence our brain and our emotions and that we are very sensitive to changes in their levels. We know that the different brain areas mature at different stages and are connected by tracts, rather like railway lines, which can sometimes go astray and lead to illnesses. And finally we know that by looking in the blood we can find clues, called biomarkers, which may ultimately help us to understand and predict brain disorders. Through this book we want to help everyone to understand the workings of the brain through pictures and cartoons. If you would like to learn more about these pictures go to our website rcsi.ie/brainjourney

Background: Studies examining individual obstetric complications with the strongest associations with schizophrenia have the potential to help elucidate the etiology of schizophrenia, both by pointing the way to molecular studies and through an examination of their synergistic interaction with other risk factors. Here, we update our previous systematic review and meta-analysis on the association between obstetric complications and schizophrenia (Cannon et al, 2002) and examine individual obstetric complications of note. Methods: We conducted a systematic review of all published literature using Medline, Embase, and PubMED, searched the reference lists of published paper, and contacted authors in the field. In keeping with our previous meta-analysis, new studies were included only if they had prospective population-based data. Obstetric complications that were examined in 2 or more studies were included. Results: Low birth-weight and unwantedness of pregnancy were examined in 2 or more population-based studies since 2002. The pooled OR for the association between low birth-weight (

This paper describes the implementation of a biochemical and biophysical screening strategy to identify and optimize small molecule Akt1 inhibitors that act through a mechanism distinct from that observed for kinase domain ATP-competitive inhibitors. With the aid of an unphosphorylated Akt1 cocrystal structure of 12j solved at 2.25 Å, it was possible to confirm that as a consequence of binding these novel inhibitors, the ATP binding cleft contained a number of hydrophobic residues that occlude ATP binding as expected. These Akt inhibitors potently inhibit intracellular Akt activation and its downstream target (PRAS40) in vitro. In vivo pharmacodynamic and pharmacokinetic studies with two examples, 12e and 12j, showed the series to be similarly effective at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice.

Objective To determine predictors of poor outcome in patients with heterotaxy syndrome. Methods A retrospective review of children with heterotaxy syndrome, in a single tertiary paediatric cardiology centre, was conducted between 1 January 1997 and 1 January 2014 to determine predictors of poor outcome. Poor outcome was defined as death, cardiac transplantation or New York Heart Association (NYHA) functional class III or IV. Results There were 35 patients diagnosed with heterotaxy syndrome, 17 of whom were diagnosed antenatally. 22 patients had right atrial isomerism and 13 had left atrial isomerism. The median age of postnatal diagnosis was 2.5 days old (1 day to 19 months). 12 patients had a poor outcome; 6 patients died, 1 underwent cardiac transplantation and 5 had an NYHA functional class of >III. 5 patients had a biventricular repair and the remaining 30 had a univentricular repair. Type of atrial isomerism, univentricular or biventricular anatomy, severity of atrioventricular valve regurgitation or ventricular dysfunction, obstructed pulmonary venous return, occurrence of arrhythmia and presence of pulmonary atresia did not predict poor outcome. Fetal diagnosis also did not confer a survival advantage. The median duration of follow-up in this cohort was 65 months (2 days to 16.8 years). Conclusions Survival for patients with heterotaxy syndrome was 83% over a median follow-up of 65 months. 34% of patients had a poor outcome. None of the variables studied were predictive of death, transplantation or NYHA classification III or IV.

A 30-year-old woman with recurring optic neuritis presented with tremor affecting her right hand when writing only (video at [Neurology.org][1]). An MRI brain (figure) revealed lesions in the left midbrain, right middle cerebellar peduncle, and left cerebellar hemisphere. [1]: http://neurology.org/lookup/doi/10.1212/WNL.0000000000003120

Herein we describe the implementation of a biochemical and biophysical screening strategy to discover small molecules that inhibit Akt through a mechanism distinct from ATP-competitive inhibitors. A series of novel derivatives of the core scaffold 3H-imidazo[4,5-b]pyridine were identified and optimized. These Akt inhibitors demonstrated potent inhibition of intracellular Akt and downstream targets including PRAS40 activation in vitro. Pharmacodynamic and pharmacokinetic studies in vivo demonstrated the effectiveness of the series at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice. Co-crystallization studies with un-phosphorylated Akt1 revealed that as a consequence of binding these novel, potent and selective, ATP-independent inhibitors the ATP binding cleft is occupied by non-polar residues which are associated as tight clusters. The cleft is closed with a ‘hydrophobic lock’ which may function to sterically exclude the binding of both ATP and ATP-competitive inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-1. doi:1538-7445.AM2012-LB-1