Citations

ABSTRACT Beyond the arboviruses they transmit to humans and animals, mosquitoes harbour diverse viral communities that shape infection and immunity dynamics. Understanding how these communities shift within mosquito populations across time and space has important implications for how we anticipate and manage arboviral disease epidemics. Here, we examined the viromes of rural and sylvatic mosquito species sampled longitudinally across two years from countries representing South America, Africa, and Southeast Asian geographies to quantify the relative contributions of host and ecological factors in shaping their virome dynamics. We found that virus diversity and virome composition are strongly influenced by host phylogeny and spatial factors and show limited temporal variation. By examining virus similarity networks across mosquito species and biogeographies, we observed frequent instances of within- and cross-genus Culex - Anopheles virus sharing in Madagascar. Taken together, these findings inform the development and implementation strategies of any virome-based vector control technology and raise new evolutionary questions on how host generalism shapes the spatial prevalence of viruses and their potential for disease emergence.

Abstract Taxanes are frontline chemotherapeutics that stabilize microtubules, induce mitotic arrest, and drive tumor remission. However, their off-target effects in healthy tissues, most notably cutaneous axon degeneration underlying chemotherapy-induced peripheral neuropathy (CIPN), remain poorly understood. Here, we show that paclitaxel induces microtubule fasciculation in epidermal keratinocytes through the mitotic kinesin Eg5, thereby initiating CIPN. Mechanistically, paclitaxel enhances Eg5-dependent fasciculation of detyrosinated (stabilized) microtubules, which constrict and breach the nuclear lamina. This deformation triggers tension-dependent NADPH oxidase-mediated nuclear ROS (X-ROS) formation upstream of mmp13 transcription, a pathway we previously demonstrated drives sensory axon degeneration. Employing a cross-species framework spanning zebrafish, mice, human skin biopsies, and a breast adenocarcinoma cell line, we uncover a conserved paclitaxel–Eg5 mechanism leading to fasciculation of stable microtubules in both healthy epidermis and cancer cells. These findings highlight the dualistic nature of paclitaxel action and underscore the challenge of preserving anticancer efficacy while preventing neurotoxic side effects.

Abstract Purpose Clozapine is primarily metabolized by cytochrome P450 (CYP) 1A2 and to a lesser extent by CYP2C19, CYP2D6, and CYP3A4. The global pandemic of coronavirus disease 2019 (COVID-19) and use of nirmatrelvir/ritonavir brought forth new challenges for those caring for patients prescribed clozapine. Prescribing information describes a consideration for a clozapine dose reduction while monitoring for adverse reactions when clozapine is used with nirmatrelvir/ritonavir. Other drug information resources consider the combination a contraindication. A case is reported in which therapeutic drug monitoring demonstrated a lack of interaction between clozapine and nirmatrelvir/ritonavir. The complexities of infection-associated clozapine toxicity are discussed and a review is provided of CYP3A4 drug and gene interactions with clozapine. Summary A 75-year-old woman with schizophrenia, prescribed clozapine 200 mg by mouth at bedtime, was initiated on nirmatrelvir/ritonavir after developing a mild COVID-19 infection. Two days later, the patient was brought to the emergency department after an unwitnessed fall. Clozapine toxicity was included in the differential diagnosis, although no other signs or symptoms of elevated clozapine levels were present. Nirmatrelvir/ritonavir was discontinued. Clozapine was withheld for 1 day while a clozapine level was pending, but this measurement revealed no interaction when compared to a baseline level of clozapine. Conclusion Although there are hypothetical concerns when initiating a CYP3A4 inhibitor with concomitant clozapine, the information derived from this case does not clearly support an interaction with the addition of nirmatrelvir/ritonavir during mild COVID-19 infection. It is important to understand the risks of withholding clozapine, although fortunately no psychiatric concerns developed. In reviewing the literature, CYP3A4 inhibitors or genetic polymorphisms seem to have a minimal impact on clozapine levels, although clinical monitoring is warranted.

A 10-year-old girl with a past medical history significant for prematurity at 29 weeks, short bowel syndrome secondary to necrotizing enterocolitis, prior episodes of small intestinal bacterial overgrowth complicated by D-lactic acidosis, and gastric tube dependence presented to an emergency department with emesis, slurred speech, somnolence, and unsteady gait. Workup was initiated, and she was started on broad-spectrum antibiotics and transferred to our pediatric intensive care unit for further evaluation and treatment. Differential diagnosis on admission was broad, and, through thorough laboratory evaluation, imaging, and multiple subspecialty inputs, an unusual diagnosis was confirmed.

Background: Autosomal recessive juvenile Parkinson disease (ARJP) is an early-onset neurodegenerative disorder characterized by Parkinsonian motor symptoms with slow progression and preserved cognition. Biallelic pathogenic variants within the PRKN gene are associated with ARJP. Among PRKN pathogenic variants, deletions are a frequent occurrence and may be identified through chromosomal microarray testing. Methods: Here we present a case with two intragenic PRKN deletions initially identified as a secondary finding using chromosomal microarray. One deletion was paternally inherited and the second initially appeared to be de novo. In addition to microarray which initially identified the two deletions, long-range GAP-PCR and Sanger sequencing were used to further characterize the de novo deletion and phase of the deletions. Results: Molecular characterization of the apparently de novo deletion demonstrated low-level maternal mosaicism of this deletion, thus proving that these deletions are in trans in the proband, yielding a diagnosis of autosomal recessive juvenile Parkinson disease. Conclusions: This case highlights the utility of a diagnostic approach combining microarray, long-range PCR, and Sanger sequencing to establish the phase and confirm biallelic PRKN deletions in a patient with ARJP. Furthermore, these findings highlight the importance of investigating the possibility of parental mosaicism to determine the phase of autosomal recessive variants and establish accurate recurrence risks.

Abstract The tumor landscape of pancreatic ductal adenocarcinoma (PDAC) is refractory to conventional photon radiotherapy (RT) due to a fibrotic tumor microenvironment (TME) that promotes chronic hypoxia and reduced immune surveillance. The radiobiological factors unique to carbon ion radiotherapy (CIRT), such as high linear energy transfer (LET) and less dependence on oxygen, make it well-suited to overcome the PDAC TME. Here, we utilized clonal syngeneic KPC pancreatic tumor cell lines and tumors to examine this postulate and to identify underlying factors that impact the response of PDAC to CIRT. While KPC cell lines exhibited radiobiologic effectiveness (RBE) greater than 3, subcutaneous tumors in the mouse hind leg showed lower RBEs – 1.3 based on quintupling time – at a LET of 75 keV/μm. Four days after CIRT, we observed widespread transcriptomic changes in the tumor immune microenvironment (TME), suggesting increased infiltration of anti-tumor immune cells, elevated expression of anti-tumor T cell cytokines, MHC class I molecules, and co-stimulatory signals. Fewer immunologic changes were observed following photon irradiation. By seven days after CIRT, tumor-supportive transcriptomic programs characterized by pro-tumor cytokines, M2 macrophages, and cancer-associated fibroblasts (CAFs) emerged, promoting resistance and limiting the durability of tumor growth delay. These findings suggest that CIRT may offer a favorable platform compared to conventional photon radiation therapy for combining with immunotherapies. Furthermore, these data highlight the risk of using in vitro survival data alone in treatment planning and indicate that underlying TME factors impact the response of PDAC in vivo .

ABSTRACT Trimethoprim/sulfamethoxazole (TMP/SMX) prophylaxis can prevent Pneumocystis jirovecii pneumonia (PJP) and other opportunistic infections (OI). We sought to assess the frequency, causative factors, and impact of early TMP/SMX discontinuation in abdominal solid organ transplant (SOT). This is a single‐center, retrospective cohort study of abdominal SOT recipients at Mayo Clinic Arizona (MCA) between January 2021 and June 2023. Primary study goals were to determine the rate and reasons behind early TMP/SMX discontinuation and whether TMP/SMX prophylaxis was reinitiated. Secondary outcomes included mean duration of therapy, alternative prophylactic agent utilized, and incidence of TMP/SMX‐preventable OI. A total of 930 abdominal SOT recipients were included (592 kidney, 253 liver, 85 multiorgan transplants). TMP/SMX was discontinued early in 184 (20%) patients: 77 kidney, 84 liver, 23 multiorgan. Predominant reasons for discontinuation were hyperkalemia (39%) and cytopenias (35%). Median duration of TMP/SMX prophylaxis before discontinuation was 54.5 (18.0, 93.2) days. TMP/SMX was not resumed in 62% of cases (36% kidney, 89% liver, 52% multi‐organ). The predominant reason for non‐resumption was alternative prophylaxis with no clear intent to rechallenge TMP/SMX (70%). Alternative prophylaxis included pentamidine (43%), none (30%), dapsone (22%), and atovaquone (5%). Of patients reinitiated, 86% (59/69) successfully remained on TMP/SMX through the prophylaxis period. One TMP‐SMX‐preventable OI (nocardiosis) was observed in the TMP/SMX discontinuation group. TMP/SMX is often discontinued prematurely in SOT recipients without resumption despite resolution of the offending cause. TMP/SMX prophylaxis should be maintained where possible, as alternative therapy may not offer the same broad spectrum of protection against OI.

Study Design Retrospective Cohort Study. Objectives To determine if 3D printed porous titanium (Ti) cages compared to non-porous polyetheretherketone (PEEK) cages predicted improved fusion rate or clinical outcomes after transforaminal lumbar interbody fusion (TLIF). Methods All adult patients who underwent one- and two-level TLIF for degenerative conditions by a single surgeon at an academic center between 2017-2021 were retrospectively identified. Patients were dichotomized into porous Ti and non-porous PEEK interbody cage groups. Fusion status was assessed by at 6-months and 1-year postoperatively by CT Bridwell scale and flexion/extension X-Rays. Postoperative complications (CT-based subsidence, adjacent segment disease, reoperation rates) and interval changes in lumbar radiographic alignment at short- and long-term follow-up were determined. Univariate and multivariate analysis compared patient and surgical factors, fusion rates, alignment, and complications across interbody groups. Results A total of 136 patients with 169 unique fusion levels (125 Ti cages, 44 PEEK cages) met the inclusion/exclusion criteria. Ti relative to PEEK interbodies had significantly decreased surface area and increased height and lordosis. Ti cage use was associated with greater subsidence ( P < 0.001) but did not independently predict maximum subsidence on regression ( P = 0.109). In the overall cohort, there were no significant differences in fusion rates or lumbopelvic alignment between interbody groups. Reoperation (Ti: 10.9% vs PEEK: 28.6%, P = 0.026) and reoperation for pseudoarthrosis (Ti: 2.0% vs PEEK: 11.4%, P = 0.038) was significantly more likely in the PEEK relative to the Ti group. Conclusions Use of 3D printed porous Ti cages relative to non-porous PEEK cages may mitigate pseudoarthrosis related reoperation after TLIF.

Abstract In the US and globally, Black men experience the highest prostate cancer burden among all racial and ethnic groups, underscoring the urgent need for research to guide the development and implementation of culturally tailored strategies aimed at reducing disparities and improving outcomes. In response, the Inclusive Cancer Care Research Equity (iCCaRE) Consortium was created to advance health equity and reduce disparities in prostate cancer. Importantly, a Survivorship Care Plan (SCP) is recommended to educate and empower patients, enabling them to be better informed about their cancer diagnosis, treatment, and survivorship care recommendations. To date, there is no SCP targeted to Black prostate cancer survivors (CaPS) who have the greatest disparities with the poorest survivorship outcomes (ACS F&F; AACR HD Report; Fullwood, 2024). Therefore, we aimed to develop a SCP tailored for Black men. Addressing the unique needs of Black men require a genuine bidirectional relationship between scientist and the community rooted in community engaged research (CER). The SCP was first informed by the literature (Bonner, 2024) and the ASCO template (canceradvocacy.org). With input from the iCCaRE leadership and the Partnership Engagement Services (PES) Core, the Whole Person SCP better responds to the informational, clinical and quality of life needs of Black Prostate Cancer survivors. Based on CER, we included 22 diverse, Black CaPs to further guide and tailor the iCCaRE. Our findings indicate that the iCCaRE Survivorship Care Plan (SCP) enhanced the ASCO template by incorporating and expanding several unique domains, including family history, care team contacts, follow-up and surveillance, symptoms, quality of life, survivor concerns, major comorbidities, health advisories, and culturally relevant resources, creating a comprehensive, whole-person SCP tailored specifically for Black men. It is crucial to continue to improve support for clinical research and advocate for Black men and their communities to reduce prostate cancer burden. Prostate cancer also needs to include incidence, mortality, and disparities for Black men to raise awareness of scarcely studied field of Black men and prostate cancer survivorship. Citation Format: Kimlin Tam Ashing, Timethia Bonner, Ewan K. Cobran, Folakemi Odedina, Aj Merriweather, Ernie Kaninjing, Floyd Willis, Cassandra Moore, Joanne Oliver, Fornati Bedell, John McCall. Advancing health equity and reducing disparities in prostate cancer in Black men: iCCaRE [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 994.

Abstract Background: Second generation androgen receptor signaling inhibitors (ARSIs), such as abiraterone, have demonstrated improved survival in metastatic castration-resistant prostate cancer (mCRPC) patients, however, acquired resistance to these agents often arises. Novel and alternative therapies are needed to combat the ARSI resistant tumor. In the last two decades patient-derived xenograft (PDX) and PDX organoids have become pivotal models in anticancer drug development and biomarker discovery due to their ability to faithfully recapitulate the complex and heterogeneous tumor biology. Methods: We analyzed RNAseq data from mCRPC patients and corresponding PDX models (PROMOTE study, NCT #01953640) and employed L1000 Chem Perturbation down/up signatures database to find candidate drugs to overcome abiraterone resistance by reverse signature search. We then performed proliferation assay using 49 compounds in three PROMOTE-PDX organoid models (2 abiraterone-resistant and 1 abiraterone-sensitive) using our semi high-throughput drug screening platform. Results: Overall, we identified a total of 32 compounds with IC50&lt;10µM in at least one of the models, among which, 5 agents are active in all three models and 5 in at least two of the models. (Table 1). Within active compounds we find selective kinase inhibitors (BRAF, JAK2, AKT, FLT3) and histone deacetylase inhibitors (belinostat and pracinostat). Particularly interesting are two drugs that are only active in the abiraterone resistant setting but not the sensitive PDX. Conclusions: In summary, we leveraged RNAseq data from mCRPC patients and PDX models and performed a high-throughput drug screen in PDX-derived organoid models to identify potential drugs that could overcome abiraterone-resistance in lethal advanced prostate cancer. These data highlight potential drug combinations or subsequent therapeutic strategies for these patients. Citation Format: Irene Marín-Goñi, Huanyao Gao, Joachim L. Petit, Shreya Indulkar, Adam M. Kase, Cassandra N. Moore, Krishna R. Kalari, Michael T. Barrett, Richard Weinshilboum, Winston Tan, John A. Copland, Liewei Wang. Overcoming resistance in mCRPC: drug discovery using PDX models and high-throughput drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5658.