Aberrant Methylation Inactivates Transforming Growth Factor β Receptor I in Head and Neck Squamous Cell Carcinoma

Background. Alterations in TGF-β signaling are common in head and neck cancer (HNSCC). Mutations in TGF-β type II receptor (TβR-II) occur frequently in HNSCC while TGF-β type I receptor (TβR-I) mutations are rare, suggesting that other molecular alterations in the TGF-β pathway are likely. To identify abnormalities in TβR-I expression we analyzed 50 HNSCCs and correlated the results with clinical-pathologic features. Methods. Hypermethylation of TβR-I was evaluated via methylation-specific PCR (MSP) and restriction enzyme-mediated PCR (MSRE). Mutations in exons 1 and 7, mRNA and protein expression were analyzed by direct sequencing, semiquantitative RT—PCR and immunohistochemistry, respectively. Results. TβR-I expression was lost in 83% HNSCCs and was linked to DNA hypermethylation of the CpG-rich promoter region in 62% of the tumors. The variants 9A/6A and Int7G24A were found in two patients. Conclusions. This study shows that suppression of TβR-I expression in HNSCC is associated with DNA hypermethylation

Aberrant methylation inactivates transforming growth factor beta receptor I in head and neck squamous cell carcinoma

Background. Alterations in TGF-β signaling are common in head and neck cancer (HNSCC). Mutations in TGF-β type II receptor (TβR-II) occur frequently in HNSCC while TGF-β type I receptor (TβR-I) mutations are rare, suggesting that other molecular alterations in the TGF-β pathway are likely. To identify abnormalities in TβR-I expression we analyzed 50 HNSCCs and correlated the results with clinical-pathologic features. Methods. Hypermethylation of TβR-I was evaluated via methylation-specific PCR (MSP) and restriction enzyme-mediated PCR (MSRE). Mutations in exons 1 and 7, mRNA and protein expression were analyzed by direct sequencing, semiquantitative RT-PCR and immunohistochemistry, respectively. Results. TβR-I expression was lost in 83% HNSCCs and was linked to DNA hypermethylation of the CpG-rich promoter region in 62% of the tumors. The variants 9A/6A and Int7G24A were found in two patients. Conclusions. This study shows that suppression of TβR-I expression in HNSCC is associated with DNA hypermethylation

Tetrahydropyrazolo[1,5-a]Pyrimidine-3-Carboxamide and N-Benzyl-6′,7′-Dihydrospiro[Piperidine-4,4′-Thieno[3,2-c]Pyran] analogues with bactericidal efficacy against Mycobacterium tuberculosis targeting MmpL3

Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-ca​rboxamide(THPP) and N-benzyl-6′,7′-dihydrospiro[piperidine-4,​4′-thieno[3,2-c]pyran](Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This ‘genetic phenotype’ was further confirmed by a ‘chemical phenotype’, whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice

Aggressive proximal tibio-fibular joint ganglion cyst after a total knee arthroplasty--a case report

Although the knee is a common location, a ganglion cyst arising from the proximal tibio-fibular joint (PTFJ) is relatively rarer. Unique diagnostic and management difficulties are encountered as these can extend into subcutaneous tissue, or spread along peroneal muscles and nerve, or erode adjacent bone. We report here a PTFJ ganglion cyst which was indolent for at least 12 years and then caused destructive and expansile changes in the fibula over a period of 6 years after a total knee arthroplasty (TKA), simulating a malignancy. Although no wear or foreign body reaction could be shown, this alarming progression of a PTFJ ganglion cyst in the fibula after the TKA is a noteworthy association, and has not been recognized and reported before. Awareness of such a lesion can aid in the diagnosis and prevent unnecessary aggressive management

Soft-tissue amyloidoma of the extremities: a case report and review of literature

Amyloidosis is a heterogeneous group of disorders characterized by extracellular deposition of unique protein fibrils. Amyloidosis may be hereditary or acquired, and the deposits may be focal, localized, or systemic in distribution. The least common presentation of an amyloid deposition is as a discrete mass called amyloidoma or amyloid tumor. Although described at various body sites, soft-tissue amyloidoma in an extremity is exceedingly rare. We report such a case of a large amyloidoma in the thigh, which simulated a soft-tissue sarcoma. In spite of attaining a very large size over a course of more than 20 years, the clinical course and the histology of this lesion were benign. Awareness of this entity will allow this rare diagnosis to be considered, prevent confusion with malignant disease, and allow appropriate management and patient reassurance. A review of literature on soft-tissue amyloidomas of extremities is also being presented