Vedantra Pharmaceuticals (United States)

Abstract Introduction: Tumor cells often display aberrant chromosome counts, or aneuploidy, which can be exacerbated by increased chromosome missegregation rates in a condition called chromosomal instability (CIN). Despite the prevalence of CIN in solid tumors and its correlation to poor patient prognosis, understanding how CIN status affects cancer aggression remains a contested issue. In this work, we present a novel mathematical model linking missegregation levels and degree of aneuploidy to the underlying fitness landscape, and examine how these fitness landscapes can affect drug efficacy. Methods: To model how chromosome counts can shift over time, we use a partial differential equation that contains a diffusion term corresponding to chromosome missegregation and a growth term proportional to the relative fitness of a particular chromosomal distribution. Using this framework, a fitness landscape that connects chromosome count to relative fitness can be inferred from a steady-state cellular population. Fluorescence in situ hybridization (FISH) was used to track chromosome counts in both CIN and non-CIN cell lines over the course of 2 months, with data collected for chromosome 10 individually and for the group of chromosomes 1, 5, and 19. Experimental results were then analyzed using our mathematical framework to determine fitness landscapes for both CIN and non-CIN cells. Results: A partial differential equation was developed to model how chromosome counts change over time based on a diffusion-like term corresponding to lagging chromosome rate and a growth rate based on a chromosome count’s contribution to overall cellular fitness. The CIN lines exhibited chromosome count distributions that were statistically closer to normal distributions than non-CIN lines. When connected to our mathematical model, these distributions imply that the CIN lines have a flatter fitness landscape than their non-CIN counterparts. This finding reinforces the notion that CIN lines are tolerant of highly varying degrees of aneuploidy. Conclusion: Our work suggests an underlying mechanism for the clinical observation that CIN tumors are more resilient to treatment with taxanes and other microtubule or mitotic targeting drugs. The flatter fitness landscapes associated with CIN provide an explanation for why these drugs are less effective, since increasing or decreasing the number of chromosomes in a CIN line does not lead to a relatively large change in fitness. Citation Format: Kelly Brock, Marianna Kleyman, Madison Stoddard, T. Ryan Gregory, Andrew Chen, Arijit Chakravarty. Fitness landscape modeling indicates decreased effectiveness of microtubule assembly targeting drugs in tumors demonstrating chromosomal instability (CIN) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C006.

Donor-derived fecal microbiota treatments are efficacious in preventing recurrent Clostridioides difficile infection (rCDI), but they have inherently variable quality attributes, are difficult to scale and harbor the risk of pathogen transfer. In contrast, VE303 is a defined consortium of eight purified, clonal bacterial strains developed for prevention of rCDI. In the phase 2 CONSORTIUM study, high-dose VE303 was well tolerated and reduced the odds of rCDI by more than 80% compared to placebo. VE303 organisms robustly colonized the gut in the high-dose group and were among the top taxa associated with non-recurrence. Multi-omic modeling identified antibiotic history, baseline stool metabolites and serum cytokines as predictors of both on-study CDI recurrence and VE303 colonization. VE303 potentiated early recovery of the host microbiome and metabolites with increases in short-chain fatty acids, secondary bile acids and bile salt hydrolase genes after antibiotic treatment for CDI, which is considered important to prevent CDI recurrences. These results support the idea that VE303 promotes efficacy in rCDI through multiple mechanisms.

Immunotherapy-related colitis (irC) frequently emerges as an immune-related adverse event during immune checkpoint inhibitor therapy and is presumably influenced by the gut microbiota. We longitudinally studied microbiomes from 38 ICI-treated cancer patients. We compared 13 ICI-treated subjects who developed irC against 25 ICI-treated subjects who remained irC-free, along with a validation cohort. Leveraging a preclinical mouse model, predisease stools from irC subjects induced greater colitigenicity upon transfer to mice. The microbiota during the first 10 days of irC closely resembled inflammatory bowel disease microbiomes, with reduced diversity, increased Proteobacteria and Veillonella, and decreased Faecalibacterium, which normalized before irC remission. These findings highlight the irC gut microbiota as functionally distinct but phylogenetically similar to non-irC and healthy microbiomes, with the exception of an acute, transient disruption early in irC. We underscore the significance of longitudinal microbiome profiling in developing clinical avenues to detect, monitor, and mitigate irC in ICI therapy cancer patients.

Persistent colonization and outgrowth of pathogenic organisms in the intestine may occur due to long-term antibiotic usage or inflammatory conditions, which perpetuate dysregulated immunity and tissue damage1,2. Gram-negative Enterobacteriaceae gut pathobionts are particularly recalcitrant to conventional antibiotic treatment3,4, though an emerging body of evidence suggests that manipulation of the commensal microbiota may be a practical alternative therapeutic strategy5-7. In this study, we rationally isolated and down-selected commensal bacterial consortia from healthy human stool samples capable of strongly and specifically suppressing intestinal Enterobacteriaceae. One of the elaborated consortia, consisting of 18 commensal strains, effectively controlled ecological niches by regulating gluconate availability, thereby reestablishing colonization resistance and alleviating antibiotic-resistant Klebsiella-driven intestinal inflammation in mice. Harnessing these microbial activities in the form of live bacterial therapeutics may represent a promising solution to combat the growing threat of proinflammatory, antimicrobial-resistant bacterial infection.

ABSTRACTConstruction and analysis of genome-scale metabolic models (GEMs) is a well-established systems biology approach that can be used to predict metabolic and growth phenotypes. The ability of GEMs to produce mechanistic insight into microbial ecological processes makes them appealing tools that can open a range of exciting opportunities in microbiome research. Here, we briefly outline these opportunities, present current rate-limiting challenges for the trustworthy application of GEMs to microbiome research, and suggest approaches for moving the field forward.

Treatment of bacterial infections with broad-spectrum antibiotics is a strategy severely limited by the decreased ability of the perturbed resident microbiota to control expansion of antibiotic-resistant pathogens. Live biotherapeutic products (LBPs) could provide an alternative to antibiotics in infection control by restoring gut colonization resistance and controlling expansion of resistant strains, an important therapeutic need not being addressed with existing anti-infective drug modalities. We review opportunities and challenges in developing LBPs for multidrug-resistant organisms colonization and infection control, with a focus on commercial fecal microbiota transplantation-like products and defined bacterial consortia, and spanning considerations related to availability of models for rational drug candidate selection and dose regimen selection, good manufacturing practice, intellectual property, and commercial viability.

Recent archaeological evidence and the comparative method of Indo-European historical linguistics now make it possible to reconstruct the Aryan migrations into India, two separate diffusions of which merge with elements of Harappan religion in Asko Parpola’s The Roots of Hinduism: The Early Aryans and the Indus Civilization (NY: Oxford University Press, 2015).This review of Parpola’s work emphasizes the acculturation of Rigvedic and Atharvavedic traditions as represented in the depiction of Vedic rites and worship of Indra and the Aśvins (Nāsatya). After identifying archaeological cultures prior to the breakup of Proto-Indo-European linguistic unity and demarcating the two branches of the Proto-Aryan community, the role of the Vrātyas leads back to mutual encounters with the Iranian Dāsas.

BackgroundMigraine, particularly chronic migraine (CM), is underdiagnosed and undertreated worldwide. Our objective was to develop and validate a self-administered tool (ID-CM) to identify migraine and CM.MethodsID-CM was developed in four stages. (1) Expert clinicians suggested candidate items from existing instruments and experience (Delphi Panel method). (2) Candidate items were reviewed by people with CM during cognitive debriefing interviews. (3) Items were administered to a Web panel of people with severe headache to assess psychometric properties and refine ID-CM. (4) Classification accuracy was assessed using an ICHD-3β gold-standard clinician diagnosis.ResultsStages 1 and 2 identified 20 items selected for psychometric validation in stage 3 (n = 1562). The 12 psychometrically robust items from stage 3 underwent validity testing in stage 4. A scoring algorithm applied to four symptom items (moderate/severe pain intensity, photophobia, phonophobia, nausea) accurately classified most migraine cases among 111 people (sensitivity = 83.5%, specificity = 88.5%). Augmenting this algorithm with eight items assessing headache frequency, disability, medication use, and planning disruption correctly classified most CM cases (sensitivity = 80.6%, specificity = 88.6%).DiscussionID-CM is a simple yet accurate tool that correctly classifies most individuals with migraine and CM. Further testing in other settings will also be valuable.

Purpose – This paper aims to explore the following questions in the light of Swami Vivekananda’s philosophy: What will ultimately come out of human development? Is development a goal in itself or only a doorway to a higher goal called transcendence? Design/methodology/approach – A comprehensive view of human development can come only through a comprehensive understanding of human nature. Findings – What the dimensions of the human personality are and how they function in the world provide a good starting point to assess the way in which human development can be achieved. Originality/value – Vivekananda’s quest for human development was not for human development per se, but to point to its potential as a spiritual practice that makes human beings realize that they are, in fact, not human being but divine beings.