Doylestown Hospital

Human metapneumovirus (HMPV) is a major cause of respiratory infections, particularly among vulnerable populations, yet effective therapeutics remain unavailable. Monoclonal antibodies (mAbs) offer a promising approach for treatment and prevention. We describe the discovery and characterization of 4F11, a highly potent neutralizing mAb with in vitro and in vivo efficacy against HMPV. Using cryo-electron microscopy, we define a unique mechanism of binding employed by 4F11. 4F11 targets an epitope located at the apex of the prefusion F protein (site Ø) with a 1:1 stoichiometry of Fab to trimer, distinct from the 3:1 stoichiometry observed with other HMPV site Ø antibodies. Unlike other site Ø antibodies which penetrate the glycan shield between Asn57 and Asn172, 4F11 binds vertically and directly interacts with the Asn172 glycan. In vitro, 4F11 displays high neutralization potency across diverse HMPV strains. It also shows low propensity for resistance development, with only a single escape mutation (K179E) identified, a mutation not found in any published HMPV sequence to date. Viruses rescued with the K179E escape mutation have significantly decreased fitness in vitro. In male hamsters, 4F11 significantly reduces viral loads in the lungs and nasal turbinates. These findings highlight 4F11 as a promising candidate for therapeutic development.

Filicide refers to an act in which a parent kills their child. It is a complex and multifaceted phenomenon observed globally. Despite widespread occurrence, the psychodynamics of filicides remain largely unexplored. Several aspects of this phenomenon are not always found in medical textbooks or journals. This case report intends to contribute to the patterns and findings of maternal filicides. Herein, we present a case of maternal filicide followed by suicide in a state in India. The mother smothered her son using a pillow before taking her own life. Therefore, the cause of death for both the mother and her child was associated with asphyxiation. This case emphasizes the integration of autopsy findings, crime scene analysis, and psychological evaluation of the deceased mental state before death for determining the cause and manner of death in these cases. Fibers obtained from the child’s body on analysis matched with a pillow found at the crime scene. The presence of a suicide note provided a great insight into the mother’s psychological state in this case. It is our opinion that reporting these events that occurred within the family leads us to understand the motivations and warning signs of maternal filicide and could prove beneficial in the pursuit of preventive child protection measures, as well as help provide early mental health intervention aside from aiding in the investigation into the cause and manner of such deaths.

Early in the 1900s, a Philadelphia Horse Dentist apparently had a jolly sense of humor. A business card with a fun reverse is evidence of that. In 1876 Peter J. Haley, Sr. founded a veterinary horse parlor business in Philadelphia, Pennsylvania, and his sons Peter Jr. Haley and James Raymond Haley carried their father's work forward, after his death.

For over 150 years, trade cards have been cherished as collector's items, with Victorian-era dental trade cards being particularly prized for their historical and artistic significance. Among the most notable collectors of these artifacts is Dr. Ted Croll, a distinguished pediatric dentist who has dedicated a half a century to curating an extensive collection. In 2024, he generously donated his entire assemblage to the NYU College of Dentistry, ensuring its preservation for future scholarship. This paper examined the distinctive nature of Croll's Collection, its systematic organization, and its enduring value in advancing historical research and understanding within the field of the history of dentistry.

Sexually transmitted infections (STIs) and HIV disproportionately affect young people; gay, bisexual, queer, and other men who have sex with men (GBQMSM); transgender women; and persons of color. Our community-based participatory research partnership developed and implemented Impact Triad, a bilingual multilevel intervention harnessing peer navigation and mHealth to increase STI/HIV preventive behaviors and address 4 community-prioritized social determinants of health-education, employment, social support, and discrimination-among young African American/Black and Latine GBQMSM and transgender women. Fifteen community-based peer navigators were trained to work within their social networks for 12 months. Each navigator engaged 5 social network members who completed baseline and immediate post-intervention assessments (retention rate, 97.3%). Regression modeling was used to assess changes in outcomes between baseline and follow-up. Among 74 enrolled social network members, the average age was 27.8 years; 61% identified as African American/Black, 31% as Latine, and 8% as multiracial/multiethnic. The majority self-identified as cisgender men and 8% as transgender women; 78% identified as gay. About half reported monthly income below $1000.Compared with baseline, at follow-up, social network members increased: STI screening (P = 0.001), HIV testing (P = 0.001), condom use (P = 0.03), and preexposure prophylaxis use (P = 0.02). Knowledge of preexposure prophylaxis (P < 0.0001) and of community-based educational (P = 0.047), job-training (P = 0.002), and job-finding resources (P = 0.02) also increased. Social support increased (P < 0.0001) and perceived discrimination decreased (P < 0.01). Pilot findings suggest that Impact Triad is promising in increasing STI/HIV protective behaviors and addressing social determinants of health among young GBQMSM and transgender women of color; further testing is warranted.

Trois hormones de croissance à longue durée d’action (LAGH) existent pour traiter le déficit en hormone de croissance (GHD). Des études ont mis en évidence une préférence patient du traitement hebdomadaire par rapport au traitement quotidien mais jamais pour différencier les LAGH indépendamment de la fréquence d’injection. Aux États-Unis, mise en place d’une étude en 3 phases, basée sur la méthode des choix discrets (DCE). La DCE mesure et évalue les compromis réalisés lors de la prise de décision entre les différents traitements. Phase 1 : examen ciblé de la littérature afin d’identifier les attributs et les niveaux pertinents. Phase 2 : entretiens qualitatifs approfondis avec les patients GHD/soignants afin d’étayer la sélection, identifier les attributs et élaborer la DCE. Phase 3 : inclusion d’environ 120 participants (soignants d’enfants [0–11 ans], dyades soignants/adolescents [12–17 ans], patients adultes atteints de GHD [≥ 18 ans]). Des tests pilotes (entretiens cognitifs [ n = 12]) confirmeront la facilité d’utilisation de la DCE. Attendus en 2024 : (1) utilités estimées en valeur partielle à l’aide d’une estimation hiérarchique bayésienne, (2) importance relative des attributs, (3) compromis patients/soignants, (4) parts de préférence estimées pour les profils correspondant aux LAGH disponibles et changements dans les choix par ajustement des niveaux. Les résultats permettront de mieux comprendre les préférences des patients/soignants et les compromis liés aux caractéristiques des dispositifs LAGH, facilitant la prise de décision partagée entre le patient/soignant et le médecin.

Abstract Developing effective strategies for treating glioblastoma (GBM), the most common and aggressive form of brain cancer, has been a long-standing challenge. Despite rigorous treatment regimens including surgical resection with concomitant radiotherapy and chemotherapy, the prognosis for this disease remains poor, largely due to tumor recurrence, resistance to conventional therapeutics, pharmacokinetic and brain delivery challenges, and dose-limiting toxicities of existing therapies. The DNA damage response and DNA repair mechanisms such as the ataxia telangiectasia and Rad3-related (ATR) pathway are key mediators of therapeutic responses, and recent studies have shown that targeting DNA repair proteins alongside standard-of-care options is a promising anti-tumor strategy. Here, we employ a combination approach using a next-generation macrocyclic ATR inhibitor, ATRIN-333, to sensitize GBM tumors to alkylators. We establish the potency of ATRIN-333 and report a robust synergistic interaction between it and the alkylator lomustine in GBM cell-based assays and in a murine flank tumor model. This combinatorial treatment was then applied to a mouse intracranial tumor model, where we utilized a convection enhanced delivery (CED) system combined with nanoparticle technology for direct intracranial administration of ATRIN-333. ATRIN-333 was successfully encapsulated into a novel polymeric nanoparticle formulation using poly(ethylene glycol)-co-poly(ethylene brassylate-co-dioxanone) (PEG-EB-co-DO). CED of both free and encapsulated ATRIN-333 potently sensitized intracranial GBM tumors to low-dose (5 mg/kg) systemically-delivered lomustine, reducing tumor size and conferring a substantial survival benefit compared to cohorts treated with lomustine or the ATR inhibitor alone. The combination approach was well tolerated by the mice, with no hematological toxicity observed as assessed by bone marrow analysis and blood cell counts. Our results demonstrate that ATR inhibitor/lomustine combination therapy, used in conjunction with a CED platform, is a powerful avenue for GBM treatment and a viable option for potential clinical implementation. Note: AJ and TL contributed equally to this work. Citation Format: Alexander Josowitz, Teresa Lee, Ranjini K. Sundaram, Jinal Pothupitiya, Eric J. Brown, Amrita Sule, Jason Beckta, Yongheng Wang, Joseph Vacca, Oren Gilad, Ranjit S. Bindra, W Mark Saltzman. Convection enhanced delivery of a novel ATR inhibitor synergizes with systemic lomustine for improved treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7117.

Abstract Previous studies have demonstrated that WEE1 inhibitors (WEE1i) are a promising cancer therapeutic through synthetic lethality with Cyclin E overexpression. One challenge for two of the leading WEE1i, AZD1775 and ZN-c3, has been the observed off-targeting of PLK family members, namely, PLK1, PLK2 and PLK3. In addition, the therapeutic application of these inhibitors in clinical trials has been limited by adverse hematological effects, including anemia. Herein, we describe the testing of a novel WEE1i (APR-1051) that, based on preclinical studies: 1) demonstrates reduced off-targeting of PLK1, PLK2 and PLK3, and 2) has the ability to suppress the growth of CCNE1-overexpressing xenografted tumors while causing little impact on red blood cell and reticulocyte levels. APR-1051 has an IC50 of 2.2 nM for WEE1 in vitro and has shown the ability to limit the proliferation of various cancer cell lines in culture. Interestingly, the genotoxicity of APR-1051 is suppressed by increasing concentrations of PLK1 inhibitors, suggesting that off-targeting of PLK1 by other WEE1i may compromise efficacy of this targeted cancer treatment in addition to the risk of producing PLK1i-associated adverse effects. APR-1051 demonstrated effectiveness in suppressing the growth of Cyclin E-overexpressing breast and ovarian cancer cells lines, thus pinpointing Cyclin E as a potential biomarker for APR-1051 treatment. Importantly, dose and scheduling of APR-1051 that causes significant suppression of CCNE1-amplified high-grade serious ovarian cancer tumors in mice is well tolerated, with red blood cell and platelet counts remaining within non-pathogenic ranges after a 28-day treatment period. In addition, inhibition WEE1 by APR-1051 occurs at an IC50 that is 200-fold lower on average than the IC50 of hERG potassium channel inhibition, implying that APR-1051 will potentially exhibit low cardiotoxicity. APR-1051 is now progressing through IND-enabling studies. Together, these findings underscore the potential of APR-1051 as a novel WEE1i for the treatment of Cyclin E-overexpressing cancers. Citation Format: Molly M. Hansbarger, Stephen J. Rocca, Sonia Ritzmann, Joseph Vacca, Bridget Tokiwa, Jonathan Weinstein, Henry Zabierek, Justin Frye, Michael Carleton, Eric J. Brown, Oren Gilad. The novel WEE1i, APR-1051, is a potentially well tolerated and effective treatment for cyclin E-overexpressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7121.

Abstract Background: ATRN-119 is an oral and highly selective nanomolar inhibitor of Ataxia Telangiectasia and Rad3- related (ATR) kinase, an enzyme that is activated by replication stress and DNA damage and prevents the collapse of DNA replication forks into double strand breaks. ATRN-119 is being studied in advanced solid tumors with dysregulated components of the DNA damage response (DDR) based on the hypothesis that these tumors will be more susceptible to ATR inhibition. Single agent ATRN-119 demonstrates increased cytotoxicity in vitro against a broad spectrum of human colon, breast, pancreatic, sarcoma, ovarian and prostate cancer cell lines that harbor genomic alterations of DDR genes. In vivo, ATRN-119 has demonstrated tumor growth inhibition in human castration-resistant prostate cancer and human colon cancer cell line-derived xenografts (CDX) mice models, and in BRCA mutant high grade serous ovarian cancer patient derived xenografts (PDXs). Trial design: This is a first-in-human Phase 1/2a open-label study (NCT04905914) to evaluate safety, tolerability, pharmacokinetics (PK), and preliminary e!cacy of oral daily ATRN-119 in subjects with advanced solid tumors, conducted in 2 parts. Part 1 consists of a 3+3 dose escalation design at up to 6 dose levels to evaluate the tolerability, PK, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of repeated daily doses of ATRN-119. Enrollment in Part 1 is ongoing. Subjects must be ≥12 years old with advanced solid tumor, have documented DDR mutations, or advanced Merkel cell carcinoma, must have failed at least one prior standard treatment, have ECOG performance status of 0 or 1, with a life expectancy &amp;gt; 3 months. Primary objective is safety/tolerability and secondary objective is efficacy. After determination of the MTD or maximum feasible dose (MFD) in Part 1, Part 2 will enroll up to 30 additional subjects. The trial is currently recruiting across 4 locations in the United States. Clinical trial identification: ClinicalTrials.gov Identifier: NCT04905914 Citation Format: Fiona Simpkins, Reva Schneider, Amit Mahipal, Patricia LoRusso, Crystal Miller, Eric Brown, Mike Carleton, Joachim Gullbo, Nadeem Q Mirza. First in Human phase 1/2a trial of a macrocyclic ATR inhibitor (ATRN-119) in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C034.