Faculty Bibliography

Human gut commensals are increasingly suggested to impact non-communicable diseases, such as inflammatory bowel diseases (IBD), yet their targeted suppression remains a daunting unmet challenge. In four geographically distinct IBD cohorts (n = 537), we identify a clade of Klebsiella pneumoniae (Kp) strains, featuring a unique antibiotics resistance and mobilome signature, to be strongly associated with disease exacerbation and severity. Transfer of clinical IBD-associated Kp strains into colitis-prone, germ-free, and colonized mice enhances intestinal inflammation. Stepwise generation of a lytic five-phage combination, targeting sensitive and resistant IBD-associated Kp clade members through distinct mechanisms, enables effective Kp suppression in colitis-prone mice, driving an attenuated inflammation and disease severity. Proof-of-concept assessment of Kp-targeting phages in an artificial human gut and in healthy volunteers demonstrates gastric acid-dependent phage resilience, safety, and viability in the lower gut. Collectively, we demonstrate the feasibility of orally administered combination phage therapy in avoiding resistance, while effectively inhibiting non-communicable disease-contributing pathobionts.

SUMMARY/CONCLUSIONS:This case presentation described a technique for repairing an acute quadriceps tendon rupture with suture anchors. The patient was a 51-year-old man who sustained an acute quadriceps tendon rupture after a fall. We used a midline incision over the quadriceps tendon and muscle. The tendon was found to be completely avulsed from the superior border of the patella. Three suture anchors were used to re-approximate the quadriceps tendon to the patella and additional sutures were used to repair the medial and lateral patellar retinacula. The patient had excellent range of motion at his 6-week follow-up appointment after the procedure.

Recent work identifies TMBIM5 as inner mitochondrial membrane Ca²⁺ /H⁺ exchanger, linking hyperpolarisation regulation to proteome control and energy metabolism.

Stem cell - like tumor propagating cells self-renew to drive clonal expansion or differentiate into post-mitotic cells without tumorigenic potential in squamous cell carcinomas. This fate choice is governed by a transcriptional network comprised of SOX2-PITX1-TP63 driven self-renewal and KLF4 dependent differentiation circuits. Yet, how stem cell - like tumor propagating cells switch from self-renewal to differentiation remains elusive. Here, we report that this cell fate choice is governed by a bi-stable Klf4 enhancer that is occupied by the transcription factor SOX2 in self-renewing or KLF4 in differentiating squamous cell carcinoma cells, dependent on whether SOX2 is phosphorylated. We will present proteomic, transcriptomic, chromatin immunoprecipitation sequencing, chromatin conformation capture sequencing, and conditional gene targeting data leading to the discovery of a molecular mechanism that governs self-renewal, differentiation, squamous cell carcinoma promotion and growth. The identified mechanism provides a novel path towards the future development of differentiation therapies that could inhibit squamous carcinogenesis in patients.
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Textured breast implants are associated with prolonged inflammation leading to increased risk for complications such as the development of anaplastic large cell lymphoma. The underlying molecular mechanisms that drive increased inflammation toward textured implants (compared with smooth implants) remain poorly understood. Here, we present the first known case of a patient with Ehlers-Danlos syndrome (EDS) who developed two independent fibrotic capsules around a single textured silicone implant. The patient was found to have one internal capsule tightly adherent to the implant and a second external capsule that was attached to the surrounding tissue. We observed that the internal implant-adherent capsule was composed of a highly aligned and dense collagen network, completely atypical for EDS and indicative of a high mechanical stress environment. In contrast, the external nonadherent capsule, which primarily interacted with the smooth surface of the internal capsule, displayed disorganized collagen fibers with no discernible alignment, classic for EDS. Remarkably, we found that the internal capsule displayed high activation of monocyte chemoattractant protein-1, a mechanoresponsive inflammatory mediator that was not elevated in the disorganized external capsule. Taken together, these findings demonstrate that the tight adhesion between the textured implant surface and the internal capsule creates a high mechanical stress environment, which is responsible for the increased local inflammation observed in the internal capsule. This unique case demonstrates that mechanical stress is able to override genetic defects locally in collagen organization and directly connects the textured surface of implants to prolonged inflammation.

The regression, or resolution, of inflammation in atherosclerotic plaques is impaired in diabetes. However, the factors mediating this effect remain incomplete. We identified protein arginine methyltransferase 2 (PRMT2) as a protein whose expression in macrophages is reduced in hyperglycemia and diabetes. PRMT2 catalyzes arginine methylation to target proteins to modulate gene expression. Because PRMT2 expression is reduced in cells in hyperglycemia, we wanted to determine whether PRMT2 plays a causal role in the impairment of atherosclerosis regression in diabetes. We, therefore, examined the consequence of deleting PRMT2 in myeloid cells during the regression of atherosclerosis in normal and diabetic mice. Remarkably, we found significant impairment of atherosclerosis regression under normoglycemic conditions in mice lacking PRMT2 (Prmt2^-/-) in myeloid cells that mimic the decrease in regression of atherosclerosis in WT mice under diabetic conditions. This was associated with increased plaque macrophage retention, as well as increased apoptosis and necrosis. PRMT2-deficient plaque CD68+ cells under normoglycemic conditions showed increased expression of genes involved in cytokine signaling and inflammation compared to WT cells. Consistently, Prmt2^-/- bone marrow-derived macrophages (BMDMs) showed an increased response of proinflammatory genes to LPS and a decreased response of inflammation resolving genes to IL-4. This increased response to LPS in Prmt2^-/- BMDMs occurs via enhanced NF-kappa B activity. Thus, the loss of PRMT2 is causally linked to impaired atherosclerosis regression via a heightened inflammatory response in macrophages. That PRMT2 expression was lower in myeloid cells in plaques from human subjects with diabetes supports the relevance of our findings to human atherosclerosis.

Aerobic exercise is associated with decreased cancer incidence and cancer-associated mortality. However, little is known about the effects of exercise on pancreatic ductal adenocarcinoma (PDA), a disease for which current therapeutic options are limited. Herein, we show that aerobic exercise reduces PDA tumor growth, by modulating systemic and intra-tumoral immunity. Mechanistically, exercise promotes immune mobilization and accumulation of tumor-infiltrating IL15Rα⁺ CD8 T cells, which are responsible for the tumor-protective effects. In clinical samples, an exercise-dependent increase of intra-tumoral CD8 T cells is also observed. Underscoring the translational potential of the interleukin (IL)-15/IL-15Rα axis, IL-15 super-agonist (NIZ985) treatment attenuates tumor growth, prolongs survival, and enhances sensitivity to chemotherapy. Finally, exercise or NIZ985 both sensitize pancreatic tumors to αPD-1, with improved anti-tumor and survival benefits. Collectively, our findings highlight the therapeutic potential of an exercise-oncology axis and identify IL-15 activation as a promising treatment strategy for this deadly disease.