💬 Editorial: Precision adjuvant therapy for stage III ColonCancer may be enhanced through molecular profiling for ctDNA status and PIK3CA mutation, informing use of celecoxib or aspirin alongside standard treatment.

CALGB/SWOG 80,702 Alliance was a placebo-controlled randomized clinical trial (RCT) of daily celecoxib (400 mg/d vs placebo) as an adjuvant therapy to fluorouracil, leucovorin, and oxaliplatin (FOLFOX) toward improving disease-free survival (DFS) of minimal residual localized (stage III) metastatic colon cancer.¹ The rationale for the trial was a preponderance of evidence from RCTs and observational studies showing that selective cyclooxygenase 2 (COX-2 or prostaglandin-endoperoxide synthase 2 [PTGS2]) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs) such as celecoxib and rofecoxib, reduce the incidence of premalignant colorectal polyps and colorectal cancer (CRC). Although the primary trial results did not show daily celecoxib to be statistically significantly associated with improvement in DFS or overall survival (OS),¹ the results raised the possibility that yet-to-be-determined subgroups may experience a significant benefit. Indeed, Nowak et al² reported in 2024 that a significant protective effect was observed among patients with tumors harboring mutations to exons 9 or 20 of the PIK3CA gene within the subset of the Alliance trial population with available whole-exome tumor sequencing data.

The possibility for molecular selection for NSAID adjuvant therapy of CRC, specifically on the basis of PIK3CA mutation was first raised in a prospective observational study by Liao and colleagues³ in 2012 for aspirin—a less selective COX-2 inhibitor. This finding for aspirin was later corroborated with post hoc observational follow-up of the VICTOR RCT of daily rofecoxib (20 mg vs placebo),⁴ which, like the Alliance trial, did not demonstrate a significant protective benefit for rofecoxib among unselected patients.⁵ Most recently, 2 RCTs of daily low-dose aspirin, ALASSCA⁶ and SAKK41/13,⁷ showed that aspirin, among patients enrolled using molecular selection for tumor PIK3CA mutation, led to a similar survival benefit of approximately 50% compared to placebo.

This case report describes a patient with X-linked FHL1-related myofibrillar myopathy and Charcot-Marie-Tooth disease type 1A, a dual pathology revealed by imaging and genetic testing.

If cancer’s genetic off switch is found then even Covid 19s off switch could essentially be found aswell.

Gene expression, where cells use the genetic information encoded in DNA to produce proteins, has been thought of as a dimmer light.

How much a particular gene gets expressed continually rises and falls, depending on the needs of a cell at any given time. It’s like adjusting the lighting of a room until it’s just right for your mood.

But University at Buffalo researchers have shown that a considerable portion of a human’s roughly 20,000 genes express more like your standard light switch — fully on or fully off.

Dominic P. Golec, Pamela L. Schwartzberg and colleagues (National Institute of Allergy and Infectious Diseases (NIAID)) describe a PI3 Kinase-Foxo1-FasL signaling circuit that promotes amplified signaling and rewires transcriptional and epigenetic programs driving IFN-γ and altered T helper cell differentiation in CD4+ T cells from mice expressing an activating mutant of phosphoinositide 3-kinase delta.

Immunodeficiency LymphocyteBiology

While inputs regulating CD4⁺ T helper (Th) cell differentiation are well defined, the integration of downstream signaling with transcriptional and epigenetic programs that define Th lineage identity remains incompletely resolved. PI3K signaling is a critical regulator of T cell function; activating mutations affecting PI3Kδ result in an immunodeficiency with multiple T cell defects. Using mice expressing activated PI3Kδ, we found aberrant expression of proinflammatory Th1 signature genes under Th2-inducing conditions, both in vivo and in vitro. This dysregulation was driven by a PI3Kδ-IL-2-Foxo1 signaling amplification loop, fueling Foxo1 inactivation, loss of Th2 lineage restriction, and extensive epigenetic reprogramming. Surprisingly, ablation of Fasl, a Foxo1-repressed gene, normalized both Th2 differentiation and TCR signaling. BioID and imaging revealed Fas interactions with TCR signaling components, which were supported by Fas-mediated potentiation of TCR signaling that could occur in the absence of FADD. Our results highlight Fas-FasL signaling as a critical intermediate in phenotypes driven by activated PI3Kδ, thereby linking two key pathways of immune dysregulation.