The success of new targeted cancer therapies has been dependent on the identification of tumor-specific antigens. Podocalyxin (Podxl) is upregulated on tumors with high metastatic index and its presence is associated with poor outcome, thus emerging as an important prognostic and theragnostic marker in several human cancers. Moreover, in human tumor xenograft models, Podxl expression promotes tumor growth and metastasis. Although a promising target for immunotherapy, the expression of Podxl on normal vascular endothelia and kidney podocytes could hamper efforts to therapeutically target this molecule. Since pathways regulating post-translational modifications are frequently perturbed in cancer cells, we sought to produce novel anti-Podxl antibodies (Abs) that selectively recognize tumor-restricted glycoepitopes on the extracellular mucin domain of Podxl.

Splenic B cells were isolated from rabbits immunized with a Podxl-expressing human tumor cell line. Abs from these B cells were screened for potent reactcacy in killing tumor cells

.

We have generated a novel and exquisitely tumor-restricted mAb, PODO447, that recognizes a glycoepitope on Podxl expressed at high levels by a variety of tumors including the majority of life-threatening high-grade serous ovarian tumors. Thus, tumor-restricted PODO447 exhibits the appropriate specificity for further development as a targeted immunotherapy.

We have generated a novel and exquisitely tumor-restricted mAb, PODO447, that recognizes a glycoepitope on Podxl expressed at high levels by a variety of tumors including the majority of life-threatening high-grade serous ovarian tumors. Thus, tumor-restricted PODO447 exhibits the appropriate specificity for further development as a targeted immunotherapy.

Checkpoint inhibitors (CPIs) such as anti-PD(L)-1 and anti-CTLA-4 antibodies have resulted in unprecedented rates of antitumor responses and extension of survival of patients with a variety of cancers. But some patients fail to respond or initially respond but later relapse as they develop resistance to immune therapy. One of the tumor-extrinsic mechanisms for resistance to immune therapy is the accumulation of regulatory T cells (T

) in tumors. In preclinical and clinical studies, it has been suggested that tumor trafficking of T

is mediated by CC chemokine receptor 4 (CCR4). Over 90% of human T

express CCR4 and migrate toward CCL17 and CCL22, two major CCR4 ligands that are either high at baseline or upregulated in tumors on CPI treatment. Hence, CCR4 antagonism has the potential to be an effective antitumor treatment by reducing the accumulation of T

into the tumor microenvironment (TME).

We developed in vitro and in vivo models to assess T

migration and antitumor efficacy using a potent and s important tumor-extrinsic mechanism for immune resistance. Blockade of CCR4 led to reduced frequency of T

and resulted in increased antitumor activity, supporting the clinical development of CCR4 inhibitors in combination with CPI for the treatment of cancer.

CPI upregulates CCL17 and CCL22 expression in tumors and increases T

migration into the TME. Pharmacological antagonism of the CCR4 receptor effectively inhibits T

recruitment and results in enhanced antitumor efficacy either as single agent in CCR4 ligand

tumors or in combination with CPIs in CCR4 ligand

tumors.

CPI upregulates CCL17 and CCL22 expression in tumors and increases Treg migration into the TME. Pharmacological antagonism of the CCR4 receptor effectively inhibits Treg recruitment and results in enhanced antitumor efficacy either as single agent in CCR4 ligandhigh tumors or in combination with CPIs in CCR4 ligandlow tumors.

To investigate timing and age distribution of atrial fibrillation (AF) in selected oncology patients, and the impact of AF timing, CHA

DS

-VASc score and cancer therapeutics on mortality.

This is a retrospective cohort study of oncology patients referred to the cardio-oncology service from 2011 to 2018 for echocardiographic cardiosurveillance and/or pre-existing cardiovascular risk factor/disease management. Rates of first AF diagnosis was assessed using a parametric multiphase hazard model (predictive modelling) and non-parametrically by Kaplan-Meier with transformations tested using a bootstrap methodology.

Among 6754 patients identified, 174 patients had their first AF diagnosis

cancer while 609 patients had their first diagnosis of AF

cancer. Most first AF diagnosis occurred at/early after cancer diagnosis. Increasing AF prevalence at time of cancer diagnosis was seen across older age groups ranges. Diagnosis of cancer at an older age and exposure to cardiotoxic treatment (anthracyclines, HEn AF and cancer. First diagnosis of AF in patients with cancer was more common at/early after cancer diagnosis, especially in older patients and those exposed to cardiotoxic treatment. Pre-existing AF or a diagnosis of AF within 3 years after cancer diagnosis carried a negative prognosis. CHA2DS2-VASc score did not relate to mortality in those that developed AF within 3 years of cancer diagnosis.

Report predictors and the natural course of paravalvular leak (PVL) following implantation of the ACURATE neo transcatheter heart valve (THV).

Understanding the mechanisms of PVL may help to improve patient selection, patient outcomes and the design of next-generation THVs.

A total of 30 patients (mean age 81±5 years, 47% women) undergoing transcatheter aortic valve replacement with the ACURATE neo were enrolled in the PREDICT PVL study. The effective regurgitant orifice area (EROA, in mm

) of PVL was assessed by transthoracic and transoesophageal echocardiography before discharge and at 6 months follow-up.

PVL was none/trace in 10 (33%), mild in 18 (60%) and moderate in 2 (7%) patients and occurred in distinct locations with largest EROAs in the area of the left coronary cusp and its adjacent commissures. Independent predictors for EROA were implantation depth (r coefficient -1.9 mm

per mm implantation depth, p=0.01), leaflet calcification (6.2 mm

per calcification grade, p=0.03) and THV size L (7.6 mm

more than size S or M, p=0.01). At 6 months follow-up, EROA decreased by 29% from 13.7±9.7 mm

to 9.5±7.9 mm

(p<0.01). Patients with smaller EROAs were more likely to be in New York Heart Association class 1 than patients with larger EROAs (p<0.01).

PVL occurred predominantly in the region of the left coronary cusp and decreased by 29% during 6 months of follow-up. Our results underscore the importance of adequate patient selection and optimal implantation depth.

PVL occurred predominantly in the region of the left coronary cusp and decreased by 29% during 6 months of follow-up. Our results underscore the importance of adequate patient selection and optimal implantation depth.Generic name Esketamine hydrochloride Brand name Spravato Formulation 28mg in 0.2ml nasal spray solution Market Authorisation holder Janssen-Cilag International NV Indication Treatment resistant major depressive disorder in adults who have failed to respond to at least two different antidepressants during the current moderate to severe episode. To be used in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin-noradrenaline reuptake inhibitor (SNRI). Dose The starting dose is 56 mg for adults aged less then 65 years and 28 mg for adults aged ≥65 years 1 Subsequent doses (56 mg or 84 mg for those less then 65 years; 28 mg, 56 mg or 84 mg for those ≥65 years) are given twice a week for 4 weeks, followed by once a week for 4 weeks, and then once a week or once every 2 weeks from week 9. Treatment is recommended for at least 6 months after symptoms improve. Cost £163 for 28 mg (one device) Classification Prescription only medicine (POM) subject to additional monitoring (▼). Controlled drug schedule 2.

Accurate documentation in healthcare is necessary for ethical, legal, research and quality improvement purposes. In this review, we aimed to evaluate the accuracy of methods of documentation of delivery room resuscitations.

A systematic literature search in MEDLINE was conducted to identify original studies that reported the quality of documentation records during newborn resuscitation in the delivery room. Data extracted from the studies included population characteristics, methodology, documentation protocols, use of gold standard and main results (initial assessment of heart rate and peripheral oxygen saturation, respiratory support and supplementary oxygen).

In total, 197 records were screened after initial database search, of which seven studies met the inclusion criteria and were finally included in this review. Four studies were chart reviews and three studies compared conventional documentation methods with video recording. Only one study tested an intervention to improve documentation. Documentation was often inaccurate and important resuscitation events and interventions were poorly recorded. Lack of uniformity among studies preclude pooled analysis, but it seems that complex or advanced procedures were more accurately reported than basic interventions.

There is little literature regarding accuracy of documentation during neonatal resuscitation, but current quality of documentation seems to be unsatisfactory. There is a need for consensus guidelines and innovative solutions in newborn resuscitation documentation.

There is little literature regarding accuracy of documentation during neonatal resuscitation, but current quality of documentation seems to be unsatisfactory. There is a need for consensus guidelines and innovative solutions in newborn resuscitation documentation.Oxygen (O2) and carbon dioxide (CO2) transport are tightly coupled in many fishes as a result of the presence of Root effect hemoglobins (Hb), whereby reduced pH reduces O2 binding even at high O2 tensions. Red blood cell carbonic anhydrase (RBC CA) activity limits the rate of intracellular acidification, yet its role in O2 delivery has been downplayed. We developed an in vitro assay to manipulate RBC CA activity while measuring Hb-O2 offloading following a physiologically relevant CO2-induced acidification. RBC CA activity in red drum (Sciaenops ocellatus) was inhibited with ethoxzolamide by 53.7±0.5%, which prompted a significant reduction in O2 offloading rate by 54.3±5.4% (P=0.0206, two-tailed paired t-test; n=7). Conversely, a 2.03-fold increase in RBC CA activity prompted a 2.14-fold increase in O2 offloading rate (P less then 0.001, two-tailed paired t-test; n=8). This approximately 11 relationship between RBC CA activity and Hb-O2 offloading rate coincided with a similar allometric scaling exponent for RBC CA activity and maximum metabolic rate. Together, our data suggest that RBC CA is rate limiting for O2 delivery in red drum.Originally described by Davis et al in 2013, 4D-Digital Subtraction Angiography (4D-DSA) has developed into a commercially available application of DSA in the angiography suite. 4D-DSA provides the user with 3D time-resolved images, allowing observation of a contrast bolus at any desired viewing angle through the vasculature and at any time point during the acquisition (any view at any time). 4D-DSA mitigates some limitations that are intrinsic to both 2D- and 3D-DSA images. The clinical applications for 4D-DSA include evaluations of AVMs and AVFs, intracranial aneurysms, and atherosclerotic occlusive disease. Recent advances in blood flow quantification using 4D-DSA indicate that these data provide both the velocity and geometric information necessary for the quantification of blood flow. In this review, we will discuss the development, acquisition, reconstruction, and current neurovascular applications of 4D-DSA volumes.