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Background This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor. Methods E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50–800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines. Results Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue ( n  = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n  = 4, 800 mg; anaphylaxis, n  = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50–800-mg oral dosing. Conclusion The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP. Clinical trial registration www.ClinicalTrials.gov code: NCT01618136.

Adaptive immune responses in humans rely on somatic genetic rearrangements of Ig and T-cell receptor loci to generate diverse antigen receptors. It is unclear to what extent an individual’s genetic background affects the characteristics of the antibody repertoire used in responding to vaccination or infection. We studied the B-cell repertoires and clonal expansions in response to attenuated varicella-zoster vaccination in four pairs of adult identical twins and found that the global antibody repertoires of twin pair members showed high similarity in antibody heavy chain V, D, and J gene segment use, and in the length and features of the complementarity-determining region 3, a major determinant of antigen binding. These twin similarities were most pronounced in the IgM-expressing B-cell pools, but were seen to a lesser extent in IgG-expressing B cells. In addition, the degree of antibody somatic mutation accumulated in the B-cell repertoire was highly correlated within twin pair members. Twin pair members had greater numbers of shared convergent antibody sequences, including mutated sequences, suggesting similarity among memory B-cell clonal lineages. Despite these similarities in the memory repertoire, the B-cell clones used in acute responses to ZOSTAVAX vaccination were largely unique to each individual. Taken together, these results suggest that the overall B-cell repertoire is significantly shaped by the underlying germ-line genome, but that stochastic or individual-specific effects dominate the selection of clones in response to an acute antigenic stimulus. Significance Human B cells secrete highly diverse antibody molecules to recognize and defend against infectious agents. Developing B cells independently rearrange their genomes to produce antibody-encoding sequences. It is uncertain to what degree genetic factors control antibody repertoires and the antibodies elicited by defined antigenic stimuli. Analysis of 134,000 antibody heavy chain sequences from genetically identical twins vaccinated with varicella-zoster vaccine indicates that twins show increased correlation in antibody gene segment usage, junctional features, and mutation rates in their antibody pools but show little similarity in clonal responses to an acute stimulus. Therefore, a shared germ-line genome sequence is correlated with overall convergence of antibody repertoires, but the particular antibody response to a given vaccination is less predictable.

ABSTRACT Upifitamab rilsodotin—an antibody drug conjugate (ADC)—comprises a NaPi2b‐targeted antibody conjugated to an auristatin‐based payload (auristatin F‐hydroxypropylamide [AF‐HPA]). AF‐HPA is metabolized by cytochrome P450 3A4 (CYP3A4) and, to a lower extent, by CYP3A5 and demonstrates both reversible and time‐dependent inhibition of CYP3A4. AF‐HPA is also a P‐glycoprotein (P‐gp) substrate. A PBPK model was developed using a mixed “bottom‐up” and “top‐down” modeling approach with a combination of in vitro, nonclinical, and clinical ADME/PK data. The model recapitulated the clinical PK of conjugated and unconjugated AF‐HPA. Simulations were used to predict the potential of unconjugated AF‐HPA to be a victim or perpetrator of clinical drug–drug interactions (DDI) and predict the impact of hepatic impairment on the exposure to unconjugated AF‐HPA. Simulations suggested negligible potential for clinical DDI between unconjugated AF‐HPA and CYP3A substrates. Simulations also showed ~30% increase in unconjugated AF‐HPA exposure following an IV dose of 36 mg/m2 in the presence of itraconazole, an inhibitor of both CYP3A4 and P‐gp. A negligible change in the exposure to unconjugated AF‐HPA was predicted in patients with mild hepatic impairment, which aligned with observed clinical data. The model predicted a ~1.5‐fold increase in unconjugated AF‐HPA AUC and negligible change in the Cmax in patients with moderate and severe hepatic impairment. Finally, this PBPK model may be applied (with modification to the conjugated drug sub‐model parameters) to predict DDI and hepatic impairment potential for other ADCs with the same linker and payload.

BackgroundSignal Transducer and Activator of Transcription 3 (STAT3), a multifaceted transcription factor, is aberrantly activated across a variety of malignancies; however, its selective targeting has to-date remained a therapeutic challenge. STAT3 plays a pivotal role in shaping the tumor immune landscape through cancer cell-intrinsic mechanisms, direct regulation of immune cell function and via cancer cell- tumor microenvironment (TME) crosstalk, that collectively result in an immunosuppressive TME. Targeted protein degradation represents a novel therapeutic modality enabling direct targeting of previously undruggable oncoproteins. We have developed potent and selective STAT3 heterobifunctional degraders demonstrating activity across diverse tumor and immune cell types.MethodsWe investigated the immunomodulatory impact of STAT3 degradation on tumorigenesis in syngeneic mouse models representing cancers with heterogeneous immune milieus. Methods included in vivo pharmacological approaches, immunophenotyping and gene expression profiling.ResultsTreatment of CT-26 (colorectal cancer) and A20 (B-cell lymphoma) tumor-bearing mice with a STAT3 degrader resulted in significant tumor growth inhibition compared to controls, with loss of STAT3 protein in both tumor cells and TME. This was accompanied by a decrease in M2 polarized macrophages and concomitant increases in M1 polarized macrophages and tumor infiltrating lymphocytes. The anti-tumor responses were abrogated by antibody mediated CD8+ T cell depletion or by using immunodeficient host-strains implicating the observed efficacy to be predominantly driven by immune-directed mechanisms. Gene expression profiling of STAT3 degrader-treated CT-26 tumors showed marked increases in proinflammatory genes including T cell and M1 macrophage activation markers, compared to controls. Notably, induction of an Ifnγ-responsive gene signature (Ifnγ, Stat1, Cxcl9, Cxcl10, Ido1) suggested that STAT3 degradation results in a T-cell inflamed phenotype associated with responsiveness to immune checkpoint therapy (ICT). Furthermore, on-treatment tumors showed an upregulation of genes such as Pdl1, Ctla4, Lag3 which reflect T cell activation as well as counterregulatory mechanisms. Therefore, we evaluated STAT3 degradation in combination with anti-PD1 in these models which are poorly responsive to anti-PD1 monotherapy. Robust synergy was observed in the CT-26 model with 60% complete responses and development of immunological memory as confirmed by tumor re-challenge studies. Studies are underway to ascertain the applicability of this combination therapy in different tumor-immune contextures and indications, and to elucidate the mechanistic basis of synergy.ConclusionsSTAT3 degradation remodels an immunosuppressed TME activating anti-tumor immunity as monotherapy and effectively combines with anti-PD1. These data provide a rationale for selectively degrading STAT3 as a strategy to sensitize cancers with relevant immune contextures to ICT in the clinic.

BackgroundOperative mortality for high-grade liver injury (HGLI) remains 42% to 66%, with near-universal mortality after retrohepatic caval injury. The objective of this study was to evaluate mortality and complications of operative and nonoperative management (OM and NOM) of HGLI at our institution, characterized by a trauma surgery–liver surgery collaborative approach to trauma care.MethodsThis was an observational cohort study of adult patients (age ≥16) with HGLI (The American Association for Surgery of Trauma (AAST) grades IV and V) admitted to an urban level I trauma center from January 2010 to November 2021. Data were obtained from the electronic medical record and state trauma registry. Patients were categorized by management strategy: immediate OM or planned NOM. The primary outcome was 30-day mortality.ResultsOur institution treated 179 patients with HGLI (78% blunt, 22% penetrating); 122 grade IV (68%) and 57 grade V (32%) injuries. All abdominal gunshot wounds and 49% of blunt injuries underwent initial OM; 51% of blunt injuries were managed initially by NOM. Procedures at the initial operation included hepatorrhaphy±packing (66.4%), nonanatomic resection (5.6%), segmentectomy (9.3%), and hepatic lobectomy (7.5%). Thirty-day mortality in the OM group was substantially lower than prior reports (23.4%). Operative mortality attributable to the liver injury was 15.7%. 19.4% of patients failed NOM with one death (1.4%).ConclusionWe report an operative mortality of 23.4% for HGLI in a trauma care system characterized by a collaborative approach by trauma surgeons and liver surgeons.Level of evidenceIII

The environmental contaminant dichloroacetate (DCA) is considered hazardous by the US environment protection agency (EPA) but is also an important drug in the clinical management of lactic acidosis. DCA has been shown to be carcinogenic in rats and causes peripheral neuropathy in humans. It is metabolized by glutathione S transferase zeta (GSTz) and inhibits its own metabolism by inactivating GSTz. This aspect of DCA metabolism is also important because GSTz also metabolizes endogenous substrates, namely maleylacetoacetate (MAA) and maleylacetone (MA), which are intermediates in tyrosine catabolism. The objectives of this research were to study the time course of inactivation and recovery of GSTz following exposure to DCA at both clinical and environmentally relevant doses and to identify possibly adducts of DCA with GSTz. Research presented here also examined the in-vivo role of MA in inactivating GSTz. Experiments conducted showed that DCA completely inactivated GSTz after one week of exposure and that enzyme recovery was not as rapid as inactivation. It took more than two weeks for the enzyme activity to return to control levels and enzyme expression remained below control levels even after eight weeks of withdrawing DCA treatment. These studies showed that enzyme recovery was slow and that the protein needed to be re-synthesized for activity to be restored. Another important finding was that environmental levels of DCA similar to those present in drinking water inactivated GSTz. Exposure of rats to DCA in drinking water at levels of 2.5 and 250 μg/kg/day significantly inhibited GSTz activity and decreased GSTz expression. Longer duration of treatment had a more prominent effect suggesting a cumulative effect. Adduct studies with recombinant hGSTz 1c-1c showed the presence of adducts of GSTz with glutathione (GSH), and glyoxalate which is the primary metabolite of DCA. Another important finding of this study was that the reactive endogenous substrate for GSTz, maleylacetone, did not inhibit GSTz activity or expression in-vivo. Previous studies with MA have shown that it inhibits GSTz in-vitro but this is the first study, to our knowledge, which showed that it was not an inhibitor of GSTz in-vivo.

Sensory appendage proteins (SAPs), members of the odorant-binding protein family, mediate chemical communication that is vital for mosquito survival and vector competence. Among the six identified SAP members, AcSAP1 and AcSAP2 exhibited dominant expression in olfactory and leg tissues of Anopheles culicifacies . Our findings reveal that the expression of AcSAP1 , and to a lesser extent AcSAP2 , is significantly modulated by the circadian rhythm, with peak expression coinciding with the nocturnal host-seeking behavior of female mosquitoes. A delayed host attraction response by the AcSAP1 -silenced female mosquitoes accounts for AcSAP1’s potential role in host-seeking activities. In silico prediction data showed strong binding affinity to synthetic pyrethroid (deltamethrin); therefore, we tested the molecular responses of SAP to insecticide exposure. Strikingly, our WHO tube test bioassay-based experimental evaluation of mosquitoes’ survival and expression modulation in the olfactory, wings, and legs highlighted SAPs’ ability to sense toxic chemical cues. Finally, coupled with confocal microscopy analysis, our notable observation of a significant increase in AcSAP1 expression in the eyes of mosquitoes challenged with deltamethrin suggests a potential role in integrating visual and chemosensory cues. Our results highlight the multifaceted functions of SAPs, demonstrating their dual roles in host-seeking and insecticide avoidance, which have significant implications for understanding mosquito biology and developing novel vector control strategies.

SARS-CoV-2 Envelope protein (E) is one of the crucial components in virus assembly and pathogenesis. The current study investigated its role in the SARS-CoV-2-mediated cell death and inflammation in lung and gastrointestinal epithelium and its effect on the gastrointestinal-lung axis. We observed that transfection of E protein increases the lysosomal pH and induces inflammation in the cell. The study utilizing Ethidium bromide/Acridine orange and Hoechst/Propidium iodide staining demonstrated necrotic cell death in E protein transfected cells. Our study revealed the role of the necroptotic marker RIPK1 in cell death. Additionally, inhibition of RIPK1 by its specific inhibitor Nec-1s exhibits recovery from cell death and inflammation manifested by reduced phosphorylation of NFκB. The E-transfected cells’ conditioned media induced inflammation with differential expression of inflammatory markers compared to direct transfection in the gastrointestinal-lung axis. In conclusion, SARS-CoV-2 E mediates inflammation and necroptosis through RIPK1, and the E-expressing cells’ secretion can modulate the gastrointestinal-lung axis. Based on the data of the present study, we believe that during severe COVID-19, necroptosis is an alternate mechanism of cell death besides ferroptosis, especially when the disease is not associated with drastic increase in serum ferritin.

AimThe insect cuticle, vital for structural maintenance, forms their exoskeleton. It is mainly composed of an intermesh of – structural cuticle proteins (CPs) with polysaccharide chitin. The insect CPs encoded by CP genes are indispensable for morphology, development and adaptation to various ecological niches across all life stages. The number of CPs may vary across genera and species, with almost 150 proteins in Bombyx mori and more than 298 CPs found in Anopheles gambiae . While they have been extensively studied in insects such as agricultural pests, limited studies have been conducted on mosquitoes, particularly those relevant to public health, such as the Anopheles a key malaria vector.ObjectiveThis review recapitulates current knowledge on CPs in insects, while also underscoring vital knowledge gaps regarding regulation and metabolic crosstalk of CPs with other signaling and/or metabolic pathways.MethodsWe performed a comprehensive review of published studies and extracted data from databases including Vectorbase and NCBI with the aim of retrieving information on cuticular proteins, their gene families, abundance and associated functions. Additionally, we identified and analyzed the gaps in the available information. A literature search was conducted between (2000 and 2025) in an electronic database using PubMed, Scopus and Google Scholar. The search keywords were: cuticular proteins, cuticular genes, Anopheles , mosquito cuticle proteins, insecticide resistance, and CP gene families.Inclusion criteria: peer-reviewed research articles and review papers particularly focused on CPs in insects and Anopheles mosquito species.ResultsIn the present review, we provide comprehensive analysis of cuticle protein families across insects including mosquitoes based on available data. We further highlight their basic constituents and protein domain structure, offering insight into their role in insect physiology. We have effectively integrated insect studies with mosquito-specific research on CPs (bridging the gap between insect and mosquito-specific research). This holistic approach would facilitate a broader comprehension of CPs in both insect and mosquito vectors.Main conclusionsThe goal of this study is to enhance our understanding of insects and Anopheles biology and how studies on CPs could be leveraged to develop novel strategy for management of pest and combat vector-borne diseases (VBDs).

Sensory appendage proteins (SAPs), members of the odorant-binding protein family, mediate chemical communication that is vital for mosquito survival and vector competence. Among the six identified SAP members, AcSAP1 and AcSAP2 exhibited dominant expression in olfactory and leg tissues of Anopheles culicifacies. Our findings reveal that the expression of AcSAP1, and to a lesser extent AcSAP2, is significantly modulated by the circadian rhythm, with peak expression coinciding with the nocturnal host-seeking behavior of female mosquitoes. A delayed host attraction response by the AcSAP1-silenced female mosquitoes accounts for AcSAP1's potential role in host-seeking activities. In silico prediction data showed strong binding affinity to synthetic pyrethroid (deltamethrin); therefore, we tested the molecular responses of SAP to insecticide exposure. Strikingly, our WHO tube test bioassay-based experimental evaluation of mosquitoes' survival and expression modulation in the olfactory, wings, and legs highlighted SAPs' ability to sense toxic chemical cues. Finally, coupled with confocal microscopy analysis, our notable observation of a significant increase in AcSAP1 expression in the eyes of mosquitoes challenged with deltamethrin suggests a potential role in integrating visual and chemosensory cues. Our results highlight the multifaceted functions of SAPs, demonstrating their dual roles in host-seeking and insecticide avoidance, which have significant implications for understanding mosquito biology and developing novel vector control strategies.