Common Partner Research Articles

Characterization of Pediatric Acute Myeloid Leukemia With t(7;12)(q36;p13).

Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is a recurrent translocation in AML in infants or very young children and was recently included in the World Health Organization (WHO) Classification of Hematolymphoid Tumors. AML with t(7;12) is reported to involve MNX1 and ETV6 signaling; however, the mechanism of leukemogenesis is not well understood, and the presence of MNX1::ETV6 fusion transcripts has only been confirmed in approximately 50% of cases. In contrast, high expression of MNX1 has been seen in all investigated cases. In this study, we investigated the clinical as well as biological characteristics of 12 pediatric AML with t(7;12) and performed whole transcriptome (WTS) and whole genome sequencing (WGS) on six of these. There was no significant difference in event-free survival or overall survival of these t(7;12) AML patients compared with other AML in the same age group. Interestingly, WTS identified several fusion transcripts involving ETV6 but not together with MNX1. WGS identified the genomic breakpoints and revealed that a common fusion partner on chromosome 7 was NOM1. Principal component analysis (PCA) of the WTS data showed that all t(7;12) AML cases cluster together, separate from all other pediatric AML subtypes; all cases had high expression of MNX1, MNX1-AS1, and MNX1-AS2. Hence, t(7;12) AML, despite expressing different fusion transcripts and with varying translocation breakpoints, constitutes a phenotypically homogenous subgroup. This underlines that the leukemia-driving event most likely is ectopic expression of MNX1 and that this therefore should be the defining Classifying criteria of this type of AML.

The enigma of KMT2A gene in hematological disorders

Abstract Introduction/Objective Presence of distinct MLL rearrangements is an independent dismal prognostic factor. Rearrangements of the histone lysine [K]- MethylTransferase 2A gene (KMT2A) on chromosome 11q23, formerly known as the mixed-lineage leukemia (MLL) gene, are found in 10% and 5% of adult and children with acute leukemia respectively. Chromosome 11 breakpoints are typically localized to band 11q23.3, frequently altering the proto- oncogene KMT2A/MLL whereas partner chromosomes involved in translocation may vary. More than 80 different gene partners involved in this fusion have been described, although the majority of leukemias results from 6 common partner genes. KMT2A gene rearrangement are associated with poor prognosis in both Lymphoid and Myeloid leukemia. Methods/Case Report A retrospective study conducted in Cytogenetic laboratory of The Indus hospital, Karachi. All karyotype cases (age 1-60 year) with chromosome 11 aberrations were included from October 2020 to December 2022. Karyotype and FISH performed using G-banding and break a part probe for MLL respectively. Results (if a Case Study enter NA) Total of 923 cases received for karyotyping out of which 32(3.4%) cases were reported for 11q23 abnormalities. The median age was 5 (1.25-12.5) years, majority 15 (47%) were 1-10 years, 9(28%) were >10 years and 7(22%) were <1 years. M:F ratio was 1.9:1. B-ALL were 19(59.4%), AML 8(25%), and 5 (15.6%) were others. FISH performed in 23(72%) cases, 21 (91%) showed concordance with karyotype. The t(9;11) was the commonest 7(22%), followed by t(4;11) and (1;11). Chromosome 9 was the most common partner identified in B-ALL. Loss of 11q23 observed in 3 (13%) cases. Conclusion The findings underscore the heterogeneity of partner chromosomes involved in KMT2A gene rearrangements and emphasize the importance of employing both FISH and karyotyping for comprehensive detection. The high concordance rate between the two methods supports their complementary roles in clinical diagnostics. Understanding the specific translocations and partner chromosomes associated with MLL gene rearrangements contributes valuable insights for prognostication and targeted therapeutic strategies in acute leukemia. FISH and karyotype showed 91% concordance to detect this aberration.

Diagnosis, Treatment Patterns, and Outcomes in Real-World Patients with RET Fusion-Positive Non-small Cell Lung Cancer in China.

Epidemiological studies on non-small cell lung cancer (NSCLC) have noted RET fusions as an oncogenic driver. However, real-world data on RET biomarker testing and treatment patterns in China remain limited. This study aimed to examine demographics, clinical and molecular features, and RET testing and treatment patterns and outcomes in patients with RET fusion-positive NSCLC. Utilizing real-world data from the Chinese Multi-center Lung Cancer Precision Medicine Registry, this retrospective cohort study focused on Chinese patients diagnosed with RET fusion-positive NSCLC between January 1, 2016, and November 30, 2021. The cohort was divided into early-stage and advanced-stage subgroups. Demographics, clinical and molecular profiles, treatment received, and outcomes including real-world event free survival (rwEFS), real-world progression free survival (rwPFS), and overall survival (OS) were assessed. The study included 121 patients with RET fusion-positive NSCLC, comprising 80 early-stage and 58 advanced-stage patients. High biomarker testing rates were observed at diagnosis (75% for early-stage, 78% for advanced-stage). RET testing was often conducted via tissue samples (95.9%) and next-generation sequencing (89.3%). KIF5B (57.0%) and CCDC6 (20.7%) were the most common gene fusion partners. The most frequent oncogenic mutations were TP53 (15.7%) and EGFR (6.6%). Platinum-based chemotherapy was the most common first-line treatment among advanced-stage patients. Median rwPFS was 9.22months for advanced-stage patients on first-line chemotherapy, and median OS was 30.7months for all advanced-stage patients. The 2-year rwEFS rate for early-stage patients was 86.0%, with a median OS of 91.9months. The study observed high biomarker testing rates at initial diagnosis for early- and advanced-stage RET fusion-positive NSCLC patients in China. The heterogeneous treatment pattern of advanced patients suggests the need for more precise, evidence-based treatment to guide clinical decisions. Given the existing therapeutic regimens fall short of adequately addressing treatment needs, targeted therapies are essential to improve outcomes.

The Partners of My Partners: Shared Collaborative Experience and Team Performance in Surgical Teams

When teams in organizations are assembled to perform contingent tasks, team members carry with them experiences of prior interaction with partners in different teams. Focal team members share collaborative experiences to the extent that they worked with common external prior partners. Extending current research on team effectiveness, we investigate how shared collaborative experience (SCE) affects team performance. Consistent with the established understanding of team processes as carrying both a teamwork and a taskwork component, we conceptualize SCE as having two distinct dimensions that we call SCE extent and SCE diversity. We posit that high SCE extent increases the ability of teams to refine their teamwork processes, increasing their performance through enhanced coordination and reflexivity. We argue that high SCE diversity hinders the ability of teams to form a shared understanding of task demands, thus undermining team performance. Furthermore, we investigate the contingent effect of task complexity on the relationship between SCE and performance. We argue that the benefits of implicit coordination and the drawbacks of experience diversity decrease as tasks become more complex and require more explicit coordination and wider repertoires of responses. These predictions find support in an analysis of 1343 robot-assisted surgery operations performed by 114 surgeons during a four-year period in a private university hospital. By explicitly recognizing how team members benefit from the network of their shared prior partners, our study contributes to developing a new approach to study the effectiveness of temporary teams in organizations.

Age and Sex Affects the Frequency and Mutation Type of FGFR2 Alterations in Cholangiocarcinoma

PURPOSE FGFR2 alterations are infrequent but currently represent the most common targetable mutation in cholangiocarcinoma. We performed a large-scale genomic analysis to assess associations between FGFR2 and other driver gene alterations in cholangiocarcinoma with patient demographics. METHODS Clinical and molecular data for patients with intrahepatic cholangiocarcinoma were abstracted from the Foundation Medicine (FMI) and Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) genomic databases. The Chi-squared test was used to assess the association between sex and alterations in driver genes. FGFR2 fusion partners were analyzed using descriptive statistics. RESULTS Across both FMI (N = 7,859) and GENIE (N = 1,395) cohorts, FGFR2 rearrangements were more frequent in female than male patients with cholangiocarcinoma (odds ratio, 1.69 and 2.45). By contrast, FGFR2 missense mutations, TP53 mutations, and KRAS mutations were not associated with sex. Stratifying patients by age groups showed that FGFR2 rearrangements were specifically enriched in younger ages (<45 years). Although the most common FGFR2 fusion partners were shared across both sexes, a subset of fusion partners was recurrent and uniquely associated with female or male patients. CONCLUSION FGFR2 rearrangements but not other driver alterations in cholangiocarcinoma are concentrated in young female patients, where the prevalence reached nearly 20% across two large patient cohorts. These results suggest that the molecular basis of FGFR2 rearrangements may be distinct between sexes. These results indicate the importance of genetic testing in cholangiocarcinoma, particularly for younger patients, and suggest that patient recruitment strategies in trials for FGFR2-targeting therapies should seek to reduce barriers to enhance the enrollment of young female patients.

Community and multisector partner engagement in US Vision Zero plan development

BackgroundVision Zero aims to eliminate serious and fatal road injuries using a Safe System approach. Safe System principles establish that safety is a shared responsibility; this involves both multisector partners...

Arthropod activity density and predation are supported by mixed cropping of maize with common sainfoin (Onobrychis viciifolia) and reduced tillage

AbstractMixed cropping with legumes may mitigate negative impacts of maize, Zea mays L. (Poaceae), production on arthropods by providing additional habitat structures and food resources. Still, knowledge about effects of less common legume partner crops for mixed cropping of maize is scarce. Activity density of epigeic predatory arthropods and proxies for ecosystem functions related to biological pest control were assessed on an experimental field. Plots of mixed cropping of maize and sainfoin, Onobrychis viciifolia Scop. (Fabaceae), and respective single plant species (plot size: 6 × 5 m; n = 48) differed in combination of the seed rate of each partner crop and tillage treatment. Using the “rapid ecosystem function assessment” approach in each plot on three occasions, we tested whether the activity density of generalist arthropod predators and their associated ecosystem functions can be promoted by mixed cropping of maize with sainfoin. Our data show that, compared with tilled maize as a pure culture, mixed cropping can increase activity density of generalist arthropod predators and insect predation potential but effects were limited to strip‐tilled cropping systems and partly depended on sampling date. Thus, from an ecological viewpoint, mixed cropping of sainfoin and maize in strip‐till systems offers the possibility to promote predatory insects and their potential for pest regulation. However, this system is inherently more prone to weed occurrence. Competition effects between cropping partners and weeds may reduce yields and hence lead to trade‐offs between enhancement of arthropods and economic viability.

Philadelphia chromosome-like acute lymphoblastic leukemia with concomitant rearrangements of CRLF2 and ABL1: a pediatric case report

BackgroundBCR::ABL1-like or Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) was first reported in 2009. Ph-like ALL is characterized by gene signature similar to Philadelphia chromosome ALL, but without BCR::ABL1 fusions. Molecularly, Ph-like ALL is divided into seven categories, with CRLF2 and ABL-class rearrangements being the two most common subtypes, exhibiting alterations in distinct downstream signaling cascades.Case presentationWe report a rare case of pediatric Ph-like ALL with concomitant CRLF2 and ABL1 rearrangements. CRLF2 was fused with P2RY8, its most common fusion partner, whereas ABL1 was fused with MYO18B, a novel fusion partner that has not been previously reported. The 4-year-old female patient was treated using the national multicenter CCCG-ALL-2020 protocol with the addition of dasatinib at the end of induction when ABL1 rearrangement was confirmed by RNA-seq. Morphologically and molecularly, the patient remained in continuous remission until the last follow-up. To the best of our knowledge, this is the first case of Ph-like ALL harboring two distinct rearrangement categories.ConclusionsOur results identified that ABL1 rearrangement and CRLF2 rearrangement can coexist. The application of FISH, whole transcription sequencing, PCR can help us to have a more comprehensive understanding of ALL cytogenetics and molecular biology. Further studies are needed to explore the role of targeted therapies in such rare clinical scenarios.

P-522 Impact of TGFß/BMP/SMAD Pathway on Premature Ovarian Insuffiency (POI)

Abstract Study question Is TGFß/BMP/SMAD pathway altered in women with POI and can results be detected from peripheral blood samples? Summary answer The TGFß/BMP/SMAD pathway mRNA-expression-alterations are detectable in leukocytes of women with Premature Ovarian Insufficiency (POI) paving the way to use it as predictive tool. What is known already A proper ovarian function relies on a complex system of signalling molecules including several BMP/TGFß-superfamily-members expressed in the ovary at different stages of folliculogenesis acting via two types of Serine/Threonine Kinase receptors. The downstream located SMAD proteins are classified into three subclasses according to their function as activated R-SMADs1,2,3,4,9, common-partner SMAD4 or inhibitory SMADs6,7. Mutations in BMPR2 and its ligands have been shown to be related to POI. Recently neurologic studies demonstrated that FMRP(Fragile-X-Mental-Retardation-1-Protein) represses BMPR2 and its gene FMR1(Fragile X Mental-Retardation-1) is one major regulator of follicular development and the most frequent genetic cause of POI if premutated. Study design, size, duration RT-q-PCR was performed to measure the mRNA-levels of SMAD 1,3,4,5, BMPR2 and FMR1. cDNA was synthesized using RNA obtained from leucocytes of patients with POI and of the control group with a normal ovarian reserve. 163 patients diagnosed with POI and 51 women in the control group were recruited between 2008 and 2022 at Heidelberg University’s Women’s Hospital. Participants/materials, setting, methods Blood samples were drawn from every participant to extract leucocyte-RNA and synthesize non-specific cDNA. RT-q-PCR was performed with TaqMan reagents to quantify relative mRNA-expression levels of SMAD 1,3,4, 5, BMPR2 and FMR1. Statistical analysis was performed with Microsoft Excel and GraphPad Prism 10 using the 2–ΔΔCt method and Mann-Whitney-Test. Statistical significance was set to p = 0.05. Main results and the role of chance In our investigation, we observed a consistent and statistically significant decrease in the expression levels of all tested SMADs—SMAD1, SMAD3, SMAD4, and SMAD5—in leukocytes of women diagnosed with POI compared to unaffected controls. The p-values amounted to p < 0.0001 for SMAD1, p = 0.0340 for SMAD3, p < 0.0001 for SMAD4, and p = 0.0076 for SMAD5. However, we did not identify notable differences in the expression levels of FMR1 and BMPR2 between the two groups. These results suggest an alteration in the regulation of the activated downstream elements SMAD 1, 3, and 5 and their common partner SMAD4 in women with POI, emphasizing its potential role as a contributing factor to diminished ovarian function. These effects seem to be independent of BMPR2 and FMR1 and regulated by other receptors and or ligands. Limitations, reasons for caution Our data are limited to mRNA-levels. So further experiments including protein-level and their phosphorylation-status are needed to receive an overall assessment of its impact on ovarian damage. It’s worth noting that the study is concentrated on leukocytes as potential diagnostic tool and results should be cross-checked in ovarian-tissue and cells. Wider implications of the findings The identified alteration in TGFß/BMP/SMAD pathway gene expression in women with POI suggest a role in ovarian damage. Lower expression levels in the aforementioned mRNAs could serve as a potential predictive biomarker for POI risks and putatively used in consultations of women prior to fertility treatment and/or preservation. Trial registration number not applicable

A hidden proteome encoded by circRNAs in human placentas: Implications for uncovering preeclampsia pathogenesis.

CircRNA-encoded proteins (CEPs) are emerging as new players in health and disease, and function as baits for the common partners of their cognate linear-spliced RNA encoded proteins (LEPs). However, their prevalence across human tissues and biological roles remain largely unexplored. The placenta is an ideal model for identifying CEPs due to its considerable protein diversity that is required to sustain fetal development during pregnancy. The aim of this study was to evaluate circRNA translation in the human placenta, and the potential roles of the CEPs in placental development and dysfunction. Multiomics approaches, including RNA sequencing, ribosome profiling, and LC-MS/MS analysis, were utilised to identify novel translational events of circRNAs in human placentas. Bioinformatics methods and the protein bait hypothesis were employed to evaluate the roles of these newly discovered CEPs in placentation and associated disorders. The pathogenic role of a recently identified CEP circPRKCB119aa in preeclampsia was investigated through qRT-PCR, Western blotting, immunofluorescence imaging and phenotypic analyses. We found that 528 placental circRNAs bound to ribosomes with active translational elongation, and 139 were translated to proteins. The CEPs showed considerable structural homology with their cognate LEPs, but are more stable, hydrophobic and have a lower molecular-weight than the latter, all of which are conducive to their function as baits. On this basis, CEPs are deduced to be closely involved in placental function. Furthermore, we focused on a novel CEP circPRKCB119aa, and illuminated its pathogenic role in preeclampsia; it enhanced trophoblast autophagy by acting as a bait to inhibit phosphorylation of the cognate linear isoform PKCβ. We discovered a hidden circRNA-encoded proteome in the human placenta, which offers new insights into the mechanisms underlying placental development, as well as placental disorders such as preeclampsia. Key points A hidden circRNA-encoded proteome in the human placenta was extensively identified and systematically characterised. The circRNA-encoded proteins (CEPs) are potentially related to placental development and associated disorders. A novel conserved CEP circPRKCB119aa enhanced trophoblast autophagy by inhibiting phosphorylation of its cognate linear-spliced isoform protein kinase C (PKC) β in preeclampsia.

Astroblastoma With a Novel YAP1::BEND2 Fusion: A Case Report.

In the most recent fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System, astroblastoma has been defined by molecular rearrangements involving the MN1 gene, with common partners being BEND2 or CXXC5 . Accordingly, this tumor entity is now known as "astroblastoma, MN1 -altered." However, gliomas with EWSR1::BEND2 fusions, devoid of MN1 fusion alterations, have recently been shown to exhibit astroblastoma-like histomorphologic features and reside in a distinct epigenetic subgroup based on DNA methylation studies similar to high-grade neuroepithelial tumor with MN1 alteration, which includes astroblastoma, MN1 altered tumors. This new epigenetically distinct subtype of astroblastoma containing EWSR1::BEND2 fusions lacks the required MN1 alteration and, thus, does not satisfy the current molecular classification of these lesions. Here, we describe a case of glioma with histologic features and DNA methylation profiling consistent with astroblastoma with a novel YAP1: : BEND2 fusion. This case and others further expand the molecular findings observable in astroblastoma-like tumors outside the constraints of MN1 alteration. Such cases of astroblastoma with EWSR1::BEND2 and YAP1::BEND2 fusions challenge the current molecular classification of astroblastoma based solely on an MN1 alteration.

Noncanonical RET fusions in Chinese patients with non-small cell lung cancer from DNA-based next-generation sequencing.

e20000 Background: The FDA has approved selpercatinib and pralsetinib for the treatment of metastatic RET fusion-positive non-small cell lung cancer in adult patients. Although the overall response rate is high and the response is durable, the outcomes may vary due to different fusion types of the same driver gene. Methods: We retrospectively collected and analyzed 14062 samples (tumour tissue or plasma) from Chinese lung cancer patients who underwent tissue-based or ctDNA-based next-generation sequencing (NGS) assays at HaploX Genomic Sequencing Center from May 18, 2020, to January 11, 2024. All samples with a RET gene fusion were included and classified based on the fusion partner gene and breakpoint position. Results: A total of 157 (1.1%) samples with DNA-based NGS harbored a RET gene fusion. Among the samples with a RET gene fusion, the most common RET fusion partners at the DNA level were KIF5B (73.2%) and CCDC6 (21.0%). We categorized RET fusions into canonical fusions and noncanonical fusions based on fusion partner and breakpoint position, and the proportions of canonical fusions and noncanonical fusions were 88.5% (139/157) and 11.5% (18/157) respectively. Among the samples with a noncanonical RET fusion, 5 samples harbored a RET fusion with an uncommon fusion partner, it remains unclear whether these fusions lead to RET activation. Conclusions: In this retrospective study, we identify different types of RET fusions in Chinese lung cancer patients. The majority are canonical fusions, which can benefit from tyrosine kinase inhibitors in clinical, the rest are noncanonical fusions, and their role in precision therapy needs further verification by RNA-based NGS or other assays. All in all, our research helps guide precision therapy in clinical settings. [Table: see text]

Distinct SAP102 and PSD-95 Nano-organization Defines Multiple Types of Synaptic Scaffold Protein Domains at Single Synapses.

MAGUK scaffold proteins play a central role in maintaining and modulating synaptic signaling, providing a framework to retain and position receptors, signaling molecules, and other synaptic components. In particular, the MAGUKs SAP102 and PSD-95 are essential for synaptic function at distinct developmental timepoints and perform both overlapping and unique roles. While their similar structures allow for common binding partners, SAP102 is expressed earlier in synapse development and is required for synaptogenesis, whereas PSD-95 expression peaks later and is associated with synapse maturation. PSD-95 and other key synaptic proteins organize into subsynaptic nanodomains that have a significant impact on synaptic transmission, but the nanoscale organization of SAP102 is unknown. How SAP102 is organized within the synapse, and how it relates spatially to PSD-95 on a nanometer scale, could underlie its unique functions and impact how SAP102 scaffolds synaptic proteins. Here we used DNA-PAINT super-resolution microscopy to measure SAP102 nano-organization and its spatial relationship to PSD-95 at individual synapses in mixed-sex rat cultured neurons. We found that like PSD-95, SAP102 accumulates in high-density subsynaptic nanoclusters (NCs). However, SAP102 NCs were smaller and denser than PSD-95 NCs across development. Additionally, only a subset of SAP102 NCs co-organized with PSD-95, revealing MAGUK nanodomains within individual synapses containing either one or both proteins. These MAGUK nanodomain types had distinct NC properties and were differentially enriched with the presynaptic release protein Munc13-1. This organization into both shared and distinct subsynaptic nanodomains may underlie the ability of SAP102 and PSD-95 to perform both common and unique synaptic functions.

Structural studies of intrinsically disordered MLL-fusion protein AF9 in complex with peptidomimetic inhibitors.

AF9 (MLLT3) and its paralog ENL(MLLT1) are members of the YEATS family of proteins with important role in transcriptional and epigenetic regulatory complexes. These proteins are two common MLL fusion partners in MLL-rearranged leukemias. The oncofusion proteins MLL-AF9/ENL recruit multiple binding partners, including the histone methyltransferase DOT1L, leading to aberrant transcriptional activation and enhancing the expression of a characteristic set of genes that drive leukemogenesis. The interaction between AF9 and DOT1L is mediated by an intrinsically disordered C-terminal ANC1 homology domain (AHD) in AF9, which undergoes folding upon binding of DOT1L and other partner proteins. We have recently reported peptidomimetics that disrupt the recruitment of DOT1L by AF9 and ENL, providing a proof-of-concept for targeting AHD and assessing its druggability. Intrinsically disordered proteins, such as AF9 AHD, are difficult to study and characterize experimentally on a structural level. In this study, we present a successful protein engineering strategy to facilitate structural investigation of the intrinsically disordered AF9 AHD domain in complex with peptidomimetic inhibitors by using maltose binding protein (MBP) as a crystallization chaperone connected with linkers of varying flexibility and length. The strategic incorporation of disulfide bonds provided diffraction-quality crystals of the two disulfide-bridged MBP-AF9 AHD fusion proteins in complex with the peptidomimetics. These successfully determined first series of 2.1-2.6 Å crystal complex structures provide high-resolution insights into the interactions between AHD and its inhibitors, shedding light on the role of AHD in recruiting various binding partner proteins. We show that the overall complex structures closely resemble the reported NMR structure of AF9 AHD/DOT1L with notable difference in the conformation of the β-hairpin region, stabilized through conserved hydrogen bonds network. These first series of AF9 AHD/peptidomimetics complex structures are providing insights of the protein-inhibitor interactions and will facilitate further development of novel inhibitors targeting the AF9/ENL AHD domain.

Unawareness of partner risk factors thwarts implementation of USPSTF recommendations for HIV pre-exposure prophylaxis in primary care

ABSTRACT The United States Preventive Services Task Force recommends pre-exposure chemoprophylaxis for persons at high risk of HIV exposure. The optimal screening strategy for at-risk individuals in primary care is not known. We evaluated the strategy of universal screening and discussed challenges to the implementation of this recommendation in primary care. Around 430 of 500 (86%) screening surveys were completed. Mutual monogamy was common but monogamous partners with recent negative HIV testing were uncommon. Likewise, among heterosexually active men and women, inconsistent condom use was common. Such individuals would be on guideline for HIV pre-exposure prophylaxis (PrEP) if their partner was at risk for HIV exposure. None of these potentially at-risk individuals met the criteria for PrEP, but 13% lacked knowledge of their partners' sexual and behavioral risk factors, preventing a clear decision on whether PrEP should be used. Our screen identified no individuals who clearly met the guideline criteria for HIV PrEP. We conclude that universal screening for HIV PrEP in primary care is unlikely to be an efficient strategy; targeted screening is likely more appropriate. Moreover, the 2019 guidelines for heterosexually active men and women rely on information that is often unknown to the patient, which makes these guidelines difficult to implement. Future guidelines should address these problems.

AN ASSESSMENT OF SOCIAL RESPONSIBILITY PROJECTS IN THE CONTEXT OF SOCIAL STATE

This study aimed to provide an account of the transformation of the social state following the enactment of neoliberal policies and the reflection of this transformation on social responsibility projects in Turkey. Employing the document analysis method, the present study examined the education-related social responsibility projects of the six companies about the cooperation in the projects, in attempts to explore whether these projects complied with the 10 high-priority targets related to education designated by Article 4 of SDGs (SDG4), which was enacted in the realm of education under the leadership of the United Nations (UN). In these projects, public institutions were the most common partners (n=13), followed by NGOs (n=5), private sector (n=3), and international institutions (n=1), respectively, whereas there was no cooperation with any institution in the four projects. The results indicated that although the projects provided a social benefit in terms of social development and integration, they remained inadequate in ensuring inclusiveness for all citizens and replacing the services carried out by the social state for the continuity and welfare of the society.

Interpersonal Abortion Conversations: Communication Characteristics Post-Roe

ABSTRACT Abortion is a politicized and stigmatized health procedure that has received considerable attention in popular discourse in the past year. The present study investigated how often people (N = 235) talk about abortion throughout their lifespan and within the past 12 months, with whom they have these conversations, and which conversations were most memorable. Key findings from the present study, framed through the Theory of Memorable Messages and the Social Ecological Model, include that most participants had at least one conversation about abortion in the past 12 months. Within the past 12 months, the most common conversation partners for abortion-related communication were friends, followed by mothers and romantic partners. Over the lifespan, but prior to the past 12 months, a majority of participants had at least one conversation about abortion. Similarly, friends were the most frequent source of abortion-related communication over the lifespan, followed by mothers and romantic partners. Many of the conversations within the past 12 months focused heavily on the overturn of Roe v. Wade or navigating a post-Roe world with a body that could become pregnant, or as someone who cared about people who could become pregnant. Prior to the past 12 months, participants characterized abortion communication as tense, religious, pro-choice, descriptive of the women who might have abortions, relating to specific abortion disclosures, or political. Within the past 12 months, memorable conversations about abortion were personal or relational, and were often prompted by discussions surrounding Roe.

TFE3 -Rearranged PEComa/PEComa-like Neoplasms : Report of 25 New Cases Expanding the Clinicopathologic Spectrum and Highlighting its Association With Prior Exposure to Chemotherapy.

Since their original description as a distinctive neoplastic entity, ~50 TFE3 -rearranged perivascular epithelioid cell tumors (PEComas) have been reported. We herein report 25 new TFE3 -rearranged PEComas and review the published literature to further investigate their clinicopathologic spectrum. Notably, 5 of the 25 cases were associated with a prior history of chemotherapy treatment for cancer. This is in keeping with prior reports, based mainly on small case series, with overall 11% of TFE3 -rearranged PEComas being diagnosed postchemotherapy. The median age of our cohort was 38 years. Most neoplasms demonstrated characteristic features such as nested architecture, epithelioid cytology, HMB45 positive, and muscle marker negative immunophenotype. SFPQ was the most common TFE3 fusion partner present in half of the cases, followed by ASPSCR1 and NONO genes. Four of 7 cases in our cohort with meaningful follow-up presented with or developed systemic metastasis, while over half of the reported cases either recurred locally, metastasized, or caused patient death. Follow-up for the remaining cases was limited (median 18.5 months), suggesting that the prognosis may be worse. Size, mitotic activity, and necrosis were correlated with aggressive behavior. There is little evidence that treatment with MTOR inhibitors, which are beneficial against TSC -mutated PEComas, is effective against TFE3 -rearranged PEComas: only one of 6 reported cases demonstrated disease stabilization. As co-expression of melanocytic and muscle markers, a hallmark of conventional TSC -mutated PEComa is uncommon in the spectrum of TFE3 -rearranged PEComa, an alternative terminology may be more appropriate, such as " TFE3 -rearranged PEComa-like neoplasms," highlighting their distinctive morphologic features and therapeutic implications.

Identification of an inhibitory pocket in falcilysin provides a new avenue for malaria drug development

Identification of new druggable protein targets remains the key challenge in the current antimalarial development efforts. Here we used mass-spectrometry-based cellular thermal shift assay (MS-CETSA) to identify potential targets of several antimalarials and drug candidates. We found that falcilysin (FLN) is a common binding partner for several drug candidates such as MK-4815, MMV000848, and MMV665806 but also interacts with quinoline drugs such as chloroquine and mefloquine. Enzymatic assays showed that these compounds can inhibit FLN proteolytic activity. Their interaction with FLN was explored systematically by isothermal titration calorimetry and X-ray crystallography, revealing a shared hydrophobic pocket in the catalytic chamber of the enzyme. Characterization of transgenic cell lines with lowered FLN expression demonstrated statistically significant increases in susceptibility toward MK-4815, MMV000848, and several quinolines. Importantly, the hydrophobic pocket of FLN appears amenable to inhibition and the structures reported here can guide the development of novel drugs against malaria.

Abstract 1981: Profiling of protein interactome with cysteine-reactive libraries led to the discovery of EML4ALK dimerizers

Abstract Cysteine covalent binders enable direct interactions with previously deemed undruggable protein targets, revolutionizing cancer therapeutics development. The primary focus has been on tailoring single-warhead compounds to target specific cysteine residues within the functional domains of target proteins. However, the biochemical properties including dimerization, induced conformational changes, and interactome disruption have been underexplored, presenting an ongoing limitation in current drug discovery approaches. In this study, we generated a library of 32 cysteine-reactive warhead compounds using various combinations of scaffolds and warheads to represent diverse reactivities. A combinatory assay approach, including cysteine druggability mapping (CDM) to discover reactive residues and SDS-PAGE fractionation assays to identify disrupted protein interaction events, was employed. Characterization of the library revealed distinct reactive cysteines and dimerization profiles among the 32 unique compounds. Compound 1C9, identified as a lead compound, demonstrated significant dimerization of EML4, a common fusion gene partner in lung cancer. Using the EML4ALK fusion gene as a proof of concept, we explored potential mechanisms underlying the compound-induced dimerization of EML4. Subsequent structure-activity relationship (SAR) studies and screening of 70 additional compounds were conducted to optimize ALK dimerization and minimize off-target effects. The enhanced compound disrupted the ALK cellular signaling pathways AKT and ERK upon dimerization of the EML4ALK fusion gene. Additionally, we discovered that covalent dimerization induced EML4ALK degradation without requiring a ubiquitin ligase like a PROTAC. In conclusion, our work has uncovered a novel class of cysteine covalent binders, which we believe are valuable tools to modulate protein-protein interactions in previously undruggable proteins in cancer. This discovery holds significant therapeutic potential for future drug development. Citation Format: Diane Yang, Stefan Harry, Elizabeth Codd, Stefan T. Kaluziak, Alexander D. Carlin, Edwin Zhang, Zavontae Oppong-Holmes, Wenxin Yang, Abigail Smith, Dawn Mitchell, Mariko Hara, Siwen Zhang, Maristela Onozato, Liron Bar-Peled, Anthony J. Iafrate. Profiling of protein interactome with cysteine-reactive libraries led to the discovery of EML4ALK dimerizers [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 1981.