Biomedical subjects

Ravindra Uppaluri

Publications and source records attributed to Ravindra Uppaluri.

5 recordsLinked to original sources

PubMed2026

Phase 1 trial and biomarker analysis of Buparlisib with weekly Cisplatin and Radiotherapy in high risk locally advanced squamous cell cancer of the Head and Neck.

PURPOSE: We evaluated the pan-PI3K inhibitor buparlisib with weekly cisplatin and radiotherapy among patients with locally advanced (LA) squamous cell cancer of the head and neck (SCCHN) and tobacco history. PATIENTS AND METHODS: Patients with stage III/IV LA-SCCHN (AJCC7), ≥10 pack-year tobacco use treated with curative intent were enrolled. Patients received buparlisib during a 2-week run-in phase and during standard 70Gy of radiotherapy plus weekly cisplatin. An exploratory analysis of genomic sequencing was performed on biopsy specimens Results: Twenty-three patients were enrolled (n=17 at the MTD (buparlisib 40 mg daily, CDDP 30mg/m2/week)). Ninety-one percent (21/23) had stage IV disease. HPV was detected in 15 of 18 cases with oral/oropharyngeal disease. 5 patients suffered recurrences of whom 3 had activating mutations along the PI3K pathway. In 5 patients whose disease responded during the 2 week run-in phase with buparlisib alone, 3 of 4 with sequencing data showed loss-of-function mutations in either Tumor Necrosis Factor Receptor Associated Factor 3 (TRAF3), and/or Cylindromatosis Lysine Deubiquinatinase (CYLD). Preclinical studies with mutations in TRAF3 or CYLD via CRISPR/Cas9 knockout in HPV+SCCHN cells demonstrate that loss of TRAF3 or CYLD may sensitize SCCHN cell lines to PI3K through mechanisms other than blocking NFκb pathway. CONCLUSIONS: Buparlisib with CRT was feasible and active, though escalation to the standard weekly cisplatin dose of 40 mg/m2 was not possible. Our data suggests that TRAF3/CYLD mutant SCCHN may be susceptible to PI3K inhibition whereas PI3K pathway activation appeared to be associated with poor outcomes in this limited dataset.

Journal Article↗

PubMed2006

Comparative analysis of regulatory and effector T cells in progressively growing versus rejecting tumors of similar origins.

Although regulatory T cells (Tregs) have been detected in clinically apparent and experimentally induced tumors, the significance of their presence is obscured because past studies examined late-stage tumors that had formed in immunocompetent hosts and thus had evolved mechanisms to escape immunologic recognition and/or elimination. Herein, we report the first comparative analysis of the antitumor response to 3'-methylcholanthrene-induced tumors, which either grow progressively (progressor tumors) or are rejected by the immune system (regressor tumors). Surprisingly, we found that both progressor and regressor tumors harbored proliferating (i.e., activated) Foxp3+CD25+Tregs. However, progressor tumors contained a higher percentage of Tregs in the lymphocyte subset versus regressor tumors. The Tregs in progressor tumors were derived from peripheral CD25+ natural Tregs, accumulated early after tumor challenge and were actively proliferating, suggesting that progressor tumors recruited and/or activated endogenous Tregs as a mechanism of escaping immune destruction. To explore whether Tregs directly contributed to the progressive growth phenotype of progressor tumors, we monitored tumor outgrowth in naive wild-type recipients pretreated with either a control monoclonal antibody (mAb) or a depleting CD25-specific mAb. In mice predepleted of CD25+ cells, the tumors that subsequently developed displayed an increased accumulation of proliferating CD8+ T cells and were rejected. These results show that, although Tregs are activated in both regressor and progressor tumors, the ratio of regulatory to effector T cells is critical in determining whether the host successfully rejects the tumor or eventually succumbs to tumor outgrowth.

Animals↗

PubMed2005

A critical function for type I interferons in cancer immunoediting.

'Cancer immunoediting' is a process wherein the immune system protects hosts against tumor development and facilitates outgrowth of tumors with reduced immunogenicity. Although interferon-gamma (IFN-gamma) is known to be involved in this process, the involvement of type I interferons (IFN-alpha/beta) has not been elucidated. We now show that, like IFN-gamma, endogenously produced IFN-alpha/beta was required for the prevention of the growth of primary carcinogen-induced and transplantable tumors. Although tumor cells are important IFN-gamma targets, they are not functionally relevant sites of the actions of the type I interferons. Instead, host hematopoietic cells are critical IFN-alpha/beta targets during development of protective antitumor responses. Therefore, type I interferons are important components of the cancer immunoediting process and function in a way that does not completely overlap the functions of IFN-gamma.

Animals↗

PubMed2005

Association of reflux with otitis media in children.

OBJECTIVES: To confirm the finding of pepsin/pepsinogen in middle ear fluid of children with chronic or recurrent otitis media (OME or ROM), and to ask parents about symptoms associated with gastroesophageal reflux (GER). METHODS: Middle ear fluid was collected from children undergoing tympanostomy tube placement. We tested this fluid for pepsin/pepsinogen using a proteolytic enzyme assay and an ELISA. Parents completed questionnaires about symptoms of GER in their children. RESULTS: We collected 36 samples from 22 children; 16 of 22 children (73%) were positive with the proteolytic assay; 17 (77%) were positive with ELISA. Questionnaires did not show increased GER symptoms. CONCLUSIONS: We replicated the finding of pepsin/pepsinogen in middle ear fluid of children with OME or ROM, but did not find any increase in GER symptoms. Further research is needed to establish a causative link between GER and OM.

Child↗

PubMed2002

IFN-producing cells respond to CXCR3 ligands in the presence of CXCL12 and secrete inflammatory chemokines upon activation.

Human natural IFN-producing cells (IPC) circulate in the blood and cluster in chronically inflamed lymph nodes around high endothelial venules (HEV). Although L-selectin, CXCR4, and CCR7 are recognized as critical IPC homing mediators, the role of CXCR3 is unclear, since IPC do not respond to CXCR3 ligands in vitro. In this study, we show that migration of murine and human IPC to CXCR3 ligands in vitro requires engagement of CXCR4 by CXCL12. We also demonstrate that CXCL12 is present in human HEV in vivo. Moreover, after interaction with pathogenic stimuli, murine and human IPC secrete high levels of inflammatory chemokines. Thus, IPC migration into inflamed lymph nodes may be initially mediated by L-selectin, CXCL12, and CXCR3 ligands. Upon pathogen encounter, IPC positioning within the lymph node may be further directed by CCR7 and IPC secretion of inflammatory chemokines may attract other IPC, promoting cluster formation in lymph nodes.

Animals↗