Development of Nanomedicine for the Treatment of Breast Cancer Metastases

RhoC-GTPase, a member of the Ras-superfamily of small guanosine triphosphatases (GTPases), is over-expressed in advanced breast cancer and has been implicated in highly motile and invasive cancer phenotypes. The overexpression of RhoC mRNA in advanced breast cancers suggests that it plays a role as a transformative oncogene for human mammary epithelial cells and as a potential marker to screen breast cancer patients with highly aggressive tumors and provide therapeutic interventions prior to the development of metastases. Short interfering RNA (siRNA) inhibits RhoC protein expression resulting in the suppression of breast cancer metastasis by inhibiting cancer cell invasion and migration. Transforming anti-RhoC siRNA into a clinically-viable therapy requires the development of biocompatible delivery systems that incorporate a large dose of siRNA and shuttle the therapeutic payload into the cytoplasm of aggressive breast cancer cells. This dissertation describes the development of peptide targeted, degradable, pH-sensitive, membrane-destabilizing β-cyclodextrin (β-CD) polymers that proved effective in condensing anti-RhoC siRNA to form “smart” nanoparticles. The peptide targeted “smart” nanoparticles facilitated selective homing into target breast cancer cells through receptor-mediated endocytosis and achieved functional delivery of anti-RhoC siRNA past the endosome into the cytoplasm of breast cancer cells resulting in the efficient knockdown of RhoC mRNA and protein levels. Specifically, we utilized the varying reactivity of the primary and secondary hydroxyl groups of the β-CD core to develop asymmetric “smart” polymers. The secondary hydroxyl groups were modified with amphiphilic copolymers comprising of pH-sensitive dimethyl aminoethyl methacrylate (DMAEMA) and hydrophobic hexyl methacrylate (HMA) monomers incorporated at a 50/50 molar feed ratio and grafted via acid-labile hydrazone linkages to form β-CD-P(HMA-co-DMAEMA) polymers. The β-CD-P(HMA-co-DMAEMA) polymers were stable at physiological pH, but rapidly degraded into membrane-active fragments at the acidic pH of the endosome. The siRNA molecules were complexed to the P(HMA-co-DMAEMA) grafts following the partial conversion of DMAEMA monomers into cationic TMAEMA monomers. The β-CD-P(HMA-co-DMAEMA-co-TMAEMA) polymers delivered anti-RhoC siRNA into the cytoplasm of SUM149 and MDA-MB-231 cells resulting in a 80-90% and 90-100% reduction in RhoC mRNA and protein levels, respectively. The incorporation of peptide targeted moieties to the free ends of polyethylene glycol (PEG) brushes on the primary face of the β-CD core resulted in selective accumulation of “smart” nanoparticles in breast cancer cells overexpressing underglycosylated Mucin 1 (uMUC1) surface receptors both in vitro and in vivo. Further, combining the peptide ligands and anti-RhoC siRNA molecules on the same asymmetric nanoparticle demonstrated a synergistic reduction in breast cancer cell invasion and migration in vitro. These results collectively confirm the successful development of a targeted, degradable “smart” nanoparticles that can enhance the functional delivery of anti-RhoC siRNA into the cytoplasm of aggressive breast cancer cell both in vitro and in vivo.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/137054/1/nkaus_1.pd

A Colossal Rhinolith

Introduction Rhinolith is a calcic deposition formed by mineralization of salts in an impacted nasal foreign body. It is a benign condition that can be troublesome owing to its size and extent of impact. Case Report A 35-year-old man with a history of right nasal obstruction with occasional foul-smelling discharge and right eye pain since ten years was diagnosed with rhinolith. During its removal, it was three times bigger than what could be visualized in nasal endoscopy. Conclusion Proper history, examination, and a high suspicion can clinch the diagnosis in almost all cases. A rigid diagnostic nasendoscopy is an important tool in the diagnosis. The treatment of choice is endoscopic removal under local or general anaesthesia

Representation of persons experiencing homelessness and coding of homelessness in general practices descriptive evaluation using healthcare utilisation data

Background Epidemiological studies focused on primary healthcare needs of persons experiencing homelessness (PEH) are often based on data from specialist homeless healthcare services. Aim To explore the presentation of PEH, coding of homelessness, and associated health conditions in mainstream primary care general practices in England. Design & setting EMIS electronic database search of medical records was conducted across 48 general practices in a clinical commissioning group (CCG), representing one of the most socioeconomically deprived regions in England, which also lacks a specialist primary healthcare service for PEH. Method Key terms and codes were used to identify PEH, their respective diagnoses across 22 health conditions, and prescribed medications over the past 4 years. Results From a population of approximately 321 000, 43 (0.013%) people were coded as PEH, compared with a homelessness prevalence of 0.5% in the English general population. Mental health conditions were the most prevalent diagnoses among the PEH registrants (56.6%); the recorded prevalence of other common long-term conditions in PEH was lower than the levels observed in PEH registered with specialist homelessness health services. Conclusion In a population with approximately four times higher rate of statutory homelessness, PEH representation in mainstream general practices was under-represented by several folds. As homelessness overlaps with mental health, substance misuse, and long-term health conditions, consistent coding of homelessness in medical records is imperative in order to offer tailored support and prevention actions when patients present for services

Cutaneous meningioma: A cytomorphological diagnosis

Cutaneous meningiomas are rare tumors. These are ectopic meningothelial cells located in the dermis and subcutis, and are usually seen on the scalp. Here, we report the case of a 40-year-old woman who presented with a slowly growing asymptomatic mass over the scalp in the right parieto-occipital region. The lesion was firm, adherent to underlying structures, and covered by normal appearing skin. The cytomorphological features along with histological and immunohistochemical studies showing positivity for epithelial membrane antigen, Vimentin, and S100 helped in making a definitive diagnosis of cutaneous meningioma. No evidence of intracranial meningioma was noted in contrast-enhanced computed tomography of the brain

Management of patients with hematological malignancies undergoing coronary artery bypass grafting

The number of patients with a previously diagnosed malignancy who need cardiac surgery is increasing. Patients with hematological malignancies represent only 0.38% of all patients undergoing cardiac surgery. The literature in this subset of patients is limited to only a few retrospective case series, with limited number of patients undergoing emergency cardiac surgery. We describe three cases with hematological malignancies namely chronic myelogenous leukemia, acute promyelocytic leukemia and chronic lymphocytic leukemia presenting for coronary artery bypass grafting (CABG). Two patients were taken up for emergency CABG in view of ongoing ischemia, one of them was on preoperative intra-aortic balloon pump support. No mortality was observed. Two patients needed transfusion of blood products which was guided by thromboelastography. One patient developed superficial sternal wound infection requiring antibiotic therapy

Isolated cutaneous cryptococcosis in clinically unsuspected idiopathic CD4 lymphocytopenia

Idiopathic CD4 lymphocytopenia first defined in 1992 by the U.S. Centers for Disease Control and Prevention, as the repeated presence of a CD4 + T-lymphocyte count of fewer than 300 cells/cumm or of <20% of total T-cells with no evidence of human immunodeficiency virus (HIV) infection and therapy that might cause depressed CD4 T-cells. Most of the cases present with systemic opportunistic infections. We report a case without risk factors or laboratory evidence of HIV infection, presenting with cutaneous cryptococcal infection, diagnosed on cytology

Isolated cutaneous cryptococcosis in clinically unsuspected idiopathic CD4 lymphocytopenia

Idiopathic CD4 lymphocytopenia first defined in 1992 by the U.S. Centers for Disease Control and Prevention, as the repeated presence of a CD4 + T-lymphocyte count of fewer than 300 cells/cumm or of <20% of total T-cells with no evidence of human immunodeficiency virus (HIV) infection and therapy that might cause depressed CD4 T-cells. Most of the cases present with systemic opportunistic infections. We report a case without risk factors or laboratory evidence of HIV infection, presenting with cutaneous cryptococcal infection, diagnosed on cytology

Management of patients with hematological malignancies undergoing coronary artery bypass grafting

The number of patients with a previously diagnosed malignancy who need cardiac surgery is increasing. Patients with hematological malignancies represent only 0.38% of all patients undergoing cardiac surgery. The literature in this subset of patients is limited to only a few retrospective case series, with limited number of patients undergoing emergency cardiac surgery. We describe three cases with hematological malignancies namely chronic myelogenous leukemia, acute promyelocytic leukemia and chronic lymphocytic leukemia presenting for coronary artery bypass grafting (CABG). Two patients were taken up for emergency CABG in view of ongoing ischemia, one of them was on preoperative intra-aortic balloon pump support. No mortality was observed. Two patients needed transfusion of blood products which was guided by thromboelastography. One patient developed superficial sternal wound infection requiring antibiotic therapy