CC-96673 (BMS-986358), an affinity-tuned anti-CD47 and CD20 bispecific antibody with fully functional fc, selectively targets and depletes non-Hodgkin's lymphoma.

Cluster of differentiation 47 (CD47) is a transmembrane protein highly expressed in tumor cells that interacts with signal regulatory protein alpha (SIRPα) and triggers a "don't eat me" signal to the macrophage, inhibiting phagocytosis and enabling tumor escape from immunosurveillance. The CD47-SIRPα axis has become an important target for cancer immunotherapy. To date, the advancement of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hematologic toxicity including anemia. To overcome those challenges a bispecific approach was taken. CC-96673, a humanized IgG1 bispecific antibody co-targeting CD47 and CD20, is designed to bind CD20 with high affinity and CD47 with optimally lowered affinity. As a result of the detuned CD47 affinity, CC-96673 selectively binds to CD20-expressing cells, blocking the interaction of CD47 with SIRPα. This increased selectivity of CC-96673 over monospecific anti-CD47 approaches allows for the use of wild-type IgG1 Fc, which engages activating crystallizable fragment gamma receptors (FcγRs) to fully potentiate macrophages to engulf and destroy CD20+ cells, while sparing CD47+CD20- normal cells. The combined targeting of anti-CD20 and anti-CD47 results in enhanced anti- tumor activity compared to anti-CD20 targeting antibodies alone. Furthermore, preclinical studies have demonstrated that CC-96673 exhibits acceptable pharmacokinetic properties with a favorable toxicity profile in non-human primates. Collectively, these findings define CC-96673 as a promising CD47 × CD20 bispecific antibody that selectively destroys CD20+ cancer cells via enhanced phagocytosis and other effector functions.

The Evolutionary History of a DNA Methylase Reveals Frequent Horizontal Transfer and Within-Gene Recombination.

Inteins, often referred to as protein introns, are highly mobile genetic elements that invade conserved genes throughout the tree of life. Inteins have been found to invade a wide variety of key genes within actinophages. While in the process of conducting a survey of these inteins in actinophages, we discovered that one protein family of methylases contained a putative intein, and two other unique insertion elements. These methylases are known to occur commonly in phages as orphan methylases (possibly as a form of resistance to restriction-modification systems). We found that the methylase family is not conserved within phage clusters and has a disparate distribution across divergent phage groups. We determined that two of the three insertion elements have a patchy distribution within the methylase protein family. Additionally, we found that the third insertion element is likely a second homing endonuclease, and that all three elements (the intein, the homing endonuclease, and what we refer to as the ShiLan domain) have different insertion sites that are conserved in the methylase gene family. Furthermore, we find strong evidence that both the intein and ShiLan domain are partaking in long-distance horizontal gene transfer events between divergent methylases in disparate phage hosts within the already dispersed methylase distribution. The reticulate evolutionary history of methylases and their insertion elements reveals high rates of gene transfer and within-gene recombination in actinophages.

Mother and Daughter Perspectives on Genetic Counseling and Testing of Adolescents for Hereditary Breast Cancer Risk.

OBJECTIVE: To evaluate the risks, benefits, and utility of testing for adult-onset hereditary breast and ovarian cancer (HBOC) in adolescents and young adults. STUDY DESIGN: We evaluated interest in genetic testing of adolescents for adult-onset HBOC genes through semistructured interviews with mothers and adolescents who had previously participated in breast cancer research or had pursued (mothers) clinical testing for HBOC. RESULTS: The majority of mothers (73%) and daughters (75%) were interested in the daughter having genetic testing and were motivated by the future medical utility and current social utility of relieving anxiety and allowing them to prepare. Mothers and daughters both reported that approximately 3 years in the future was the best time to test the daughter regardless of the current age of the daughter. Overall, both mothers and daughters expressed the importance of the involvement of the mother to provide educational and emotional support but ultimately it was the daughter's decision to test. Balancing the independence and maturity of the daughter while reinforcing communication and support within the dyad was a prominent theme throughout the interviews. CONCLUSIONS: There is interest among some high-risk adolescents and young adults to engage in genetic counseling and undergo testing. Providing pretest and posttest genetic counseling, assessing preferences for parent involvement, and offering psychosocial support may be important if genetic testing for HBOC is offered to adolescents and young adults before age 25 years.

Management and outcome of obstructive ureteral stones in the emergency department: Emphasis on urine tests and antibiotics usage.

BACKGROUND: Kidney stone related complaints in the Emergency Department (ED) are common. Current guidelines recommend antibiotic therapy for infected obstructive stones and stone removal in a timely fashion, but there is no clear recommendation for prophylactic antibiotic use for bacteriuria or pyuria in the setting of obstructive ureteral stones. OBJECTIVES: The aim of this study is to evaluate the current management of patients with obstructive ureteral stones in a single ED with emphasis on urine tests and antibiotics use. METHODS: The picture archiving and communication system (PACS) was used to filter the list of patients who received a computed tomography (CT) scan of the abdomen and pelvis that positively identified obstructive ureteral stones. Demographics and clinical data were also recorded and analyzed. RESULTS: Of the patients discharged, 278 patients did not receive antibiotics in the ED or a prescription. Of these, 8 patients had positive culture, 4 patients followed up, and one developed and was treated for a urinary-tract infection. One hundred ninety two patients were not given antibiotics in the ED but received an antibiotics prescription, and 4 patients had positive cultures grow. Two followed up and had no infection-related complications. Fourteen patients were discharged without a prescription after receiving a single dose of antibiotics in the ED, with no positive urine cultures and 9 patients following up without complication. CONCLUSION: Antibiotics were given at the discretion of the provider without clear pattern. A high rate of infectious complication did not occur in the followed up patient group.

Epidemiology of ambulance utilized patients in Addis Ababa, Ethiopia.

BACKGROUND: Well organized and appropriately utilized pre-hospital emergency services play a critical role in augmenting emergency care systems. The primary objective of this study was to understand the demographic and clinical profile of patients who used ambulances in Addis Ababa. The secondary objectives were to assess ambulance response time, transport time and reasons for referral amongst inter-facility transported patients in Addis Ababa. METHODS: The study was designed as a cross-sectional retrospective chart review of ambulance transported patients using ambulance station records from Addis Ababa Fire and Emergency Prevention and Control Authority. With IRB approval, simple random sampling and manual review of six months of clinical records was performed. Data were collected by trained data collectors and descriptive analysis was done using SPSS version 20. RESULTS: Female patients used ambulance services more often than males (female to male ratio of 3:1) and the mean age of the patients was 26 years. The most commonly transported age group was 16-30 years, followed by 31-50 years and neonatal patients (i.e. < 1 month). The majority of the patients had pregnancy related illnesses (n = 492, 61.4%), followed by general medical issues (n = 210, 26.2%) and injury secondary to trauma (n = 99, 12.3%). Most patients (n = 702, 87.6%) were transported for inter-facility transfers, while only 12.4% (n = 99) were primary responses (i.e. from the scene). Prolonged labor was the most common reason (n = 103, 23.4%) for inter-facility transfer of pregnant patients, followed by premature rupture of the amniotic membrane (n = 60, 13.6%). The mean dispatch to scene time interval was 10.1 min, and mean scene to facility time interval was 17.2 min. CONCLUSION: Inter-facility transfers accounted for the largest proportion of ambulance utilization and dispatch in Addis Ababa. Ambulance transport time was twice as long compared to international recommendations of less than eight minutes for emergent transports. The most common reasons for ambulance dispatch were Obstetric. We recommend urgent action to decrease the transport times and to dedicate further pre-hospital resources to address the high burden of inter-facility transfers.

Acute stent thrombosis: Should preventative measures start in the emergency department?

Stent thrombosis is a potentially life threatening condition caused by several factors or a combination factors, such as resistance to platelet agents and type of anticoagulation used as well as stent types. We report a case of acute thrombosis and discuss potential areas of intervention with literature review.