SOMATOSTATIN RECEPTOR TYPE 2 (SSTR2) FOR ADOPTIVE T CELL IMAGING, STIMULATION, AND ELIMINATION

Harnessing the immune system to recognize and destroy tumor cells has been the central goal of anti-cancer immunotherapy. Adoptive cell therapy (ACT) is a treatment that uses a cancer patient's own T lymphocytes with anti-tumor activity, expanded in-vitro and re-infused into the patient. The ability to genetically engineer human lymphocytes and use them to mediate cancer regression in patients, which has recently been demonstrated, has opened possibilities for the extension of ACT immunotherapy to patients with a wide variety of cancer types and is a promising new approach to cancer treatment. Clinical monitoring of ACT utilizes serial blood analyses to discern T cell activity. While useful, these data are 1-dimensional and lack spatiotemporal information related to treatment efficacy or toxicity. In this dissertation, I have utilized a human genetic reporter, somatostatin receptor 2 (SSTR2), and PET, to quantitatively and longitudinally visualize whole-body T cell distribution and antitumor dynamics using a clinically approved radiotracer. Initial evaluations determined that SSTR2-expressing T cells were detectable at low densities with high sensitivity and specificity. While keeping a close eye on the status of immunotherapy is shown in the early part of this thesis, later topics address the ideal antigens to target tumors, more specifically targeting solid tumors. We turned to targeting inflammation, specifically intercellular adhesion molecule-1 (ICAM-1), as an ideal marker for solid tumors. ICAM-1, which has been implicated to play a critical role in tumor progression in various types of cancer, has also been linked to cancer metastases, where this molecule facilitates the spread of metastatic cancer cells to secondary sites. The unique expression profile of ICAM-1 throughout solid tumor microenvironment makes ICAM-1 an intriguing molecular target, as evidence suggests that approximately 25% of all human cancer worldwide is associated with chronic inflammation. Utilizing ICAM1 as a target, I share the success of using an ICAM1 specific chimeric antigen receptor (CAR) T cells to eliminate anaplastic thyroid cancer tumors, in a solid tumor mouse model. The first attempt was using the single-chain fragmentvariable of R6.5, an ICAM-1 specific antibody. Followed by the utilization of the active domain (I-domain) of the natural ligand to ICAM-1, lymphocyte function associated antigen-1 (LFA-1). For I-domain CAR, many engineered affinity variants were studies, to help determine the ideal antigen to affinity, to maintain CAR T cell persistence without any systemic toxicities sometimes observed with ACTs

Intrusion of Supraerupted Maxillary First Molar Using Modified TPA and TAD's - A Simple, Clinically Efficient Approach.

The orthodontist treating adult patients often encounters a dentition that was neglected after premature loss of posterior teeth. The adjacent teeth tend to tilt and rotate, and the occluding tooth can supraerupt. This early loss of posterior teeth and a delay in replacing the missing teeth results in over eruption of antagonist teeth. Overextrusion of maxillary molars usually results from early loss of antagonistic teeth. The elongated dentoalveolar process may induce problems such as functional disturbances and occlusal interference and cause great difficulty during prosthetic reconstruction.                    This case report demonstrates the efficient use of TAD's along with modified TPA in a patient with an supraerupted maxillary first molar in a 23-year-old girl. Treatment objective was to intrude the maxillary 1st molar to facilitate prosthetic replacement of lower 1st molar. The treatment mechanics involved: 0.022 x 0.028 MBT appliance for initial leveling & aligning followed by modified TPA with soldered hook for intrusion of first maxillary left molar. A section of Elastomeric chain was stretched from the mini-implant placed in the left buccal 1st molar region to the soldered hook on the Transpalatal Arch. Activation was done every 21 days. We preferred 150 g force to intrude the molar in this study.                    Intrusion was finished when tooth was leveled with the neighboring teeth. Amount of intrusion achieved was 3 mm in a span of 6 months and to avoid root resorption, intrusive force levels was kept optimal

Pharmacovigilance in cancer chemotherapy in regional cancer center of Eastern India: prospective observational study

Background: Globally cancer is the leading cause of morbidity and mortality with annual death rate of 12%. According Indian Council of Medical Research, more than 1300 Indians die every day due to cancer. Chemotherapy is one of the multimodal approaches for treatment of cancer and regimens are much complex and cancer patients are more susceptible to adverse drug reaction with little tolerance due to diminished immunity. The present study was done to evaluate the prevalence of various adverse drug reactions with different cancer chemotherapy regimens, their nature and severity as well as their causality assessment as per WHO scale.Methods: This prospective observational study was conducted from July 2015 to June 2016. Patients receiving cancer chemotherapy from regional cancer centre, Cuttack were observed during the study period for the adverse drug reactions. Those ADRs were analysed for causality assessment, severity and preventability.Results: It was observed that after the initiation of chemotherapy, ADRs were observed in 92 (88.46%) patients. Among these 329 observed ADRs, during the study period, female predominance was observed in the age group 51-60yrs. Most common ADRs observed were nausea and vomiting 57 (17.37%), alopecia 46 (13.98%) and neutropenia 38 (11.55%). ADRs were most commonly seen with the haematological systems (37.68%) followed by gastrointestinal system amounting 25.22% of the total ADRs. Platinum Compound (58.35%), followed by antibiotics, antimetabolites, were the most common group of drugs causing different adverse drug reactions. On causality assessment, as per WHO-UMC criteria 68.38% were probable and 31.62% ADRs were possible. Severity assessment showed majority of the ADRs were moderate 228 (69.31%) followed by mild 67 (20.36%) and severe 34 (10.33%). It was observed that majority 212 (64.45%) of the ADRs were not preventable, 72 (21.88%) were definitely preventable and 45 (13.67%) were probably preventable.Conclusions: Cancer chemotherapy has definitely improved the quality of life, but associated ADRs need early diagnosis, prompt management and routine reporting. Thus, pharmacovigilance will definitely reduce morbidity and mortality, so also the financial burden for the patients and society

CoVE: Towards Confidential Computing on RISC-V Platforms

Multi-tenant computing platforms are typically comprised of several software and hardware components including platform firmware, host operating system kernel, virtualization monitor, and the actual tenant payloads that run on them (typically in a virtual machine, container, or application). This model is well established in large scale commercial deployment, but the downside is that all platform components and operators are in the Trusted Computing Base (TCB) of the tenant. This aspect is ill-suited for privacy-oriented workloads that aim to minimize the TCB footprint. Confidential computing presents a good stepping-stone towards providing a quantifiable TCB for computing. Confidential computing [1] requires the use of a HW-attested Trusted Execution Environments for data-in-use protection. The RISC-V architecture presents a strong foundation for meeting the requirements for Confidential Computing and other security paradigms in a clean slate manner. This paper describes a reference architecture and discusses ISA, non-ISA and system-on-chip (SoC) requirements for confidential computing on RISC-V Platforms. It discusses proposed ISA and non-ISA Extension for Confidential Virtual Machine for RISC-V platforms, referred to as CoVE

Whole body biomechanics of vertical ladder climbing with varying rung separations

Climbing a vertical ladder continues to be a safety concern for both manufacturer and professional users. Among these professional users are the wind service technicians who climb the wind towers greater than 80m to perform a variety of maintenance work (BLS, 2010). These technicians are getting injured at a frequent rate (USPC, 2011). Among these, musculoskeletal injuries associated with the knee joint are dominant (Reid & McMulin, 2006). Published literature on ladder climbing has mainly addressed the accidents related to slips and falls (Armstrong, 2009; McInyere, 1983; Dewar, 1977) and a few studies have addressed the musculoskeletal injuries associated with slanted ladders (Hoozemans & Louche, 2005; Bloswick, 1990). Currently a gap in the literature exists with respect to the potential risk of musculoskeletal injuries associated with vertical ladder climbing. That is the aim of this study, to predict the lower limb internal joint forces and moments during a vertical ladder climbing activity and associate the outcome of this analysis to the causes of musculoskeletal injuries. Six male and six female adult subjects participated in this study. Participants climbed an instrumented vertical laboratory ladder similar to ladders used on wind towers. Independent variables for this experiment included three levels of climbing speed, two levels of climbing direction, three levels of rung separation, three levels of subject anthropometry and two levels of gender. Dependent measures included measured hand and foot forces, predicted lower and upper joint moments and EMG activity of the lower limb flexor and extensor muscles. Synchronized kinetic and kinematic data collected during the experimental trials was provided to a two-dimensional dynamic link-segment model. The output from the model included the predicted internal forces and moments at the ankle, knee and hip joint. Results indicated climbing style, climbing speed and rung separation distance had a significant effect on predicted peak lower joint moments. Excessive muscle contractions were observed during ladder ascent than the descent for all four lower limb flexor and extensor muscles. The results concluded that climbing the ladder using side rails as support was more strenuous than climbing the ladder with rungs as support

Hemifacial atrophy

We report the case of a 44-year-old woman with a one-year history of en coup de sabre morphea and progressive hemifacial atrophy with ipsilateral hemifacial neuralgia, migraine, and contralateral neurologic abnormalities. While rare, Parry-Romberg syndrome typically presents in the first or second decade of life; this patient’s case is unusual in that the onset of her disease is demonstrated at age 43. Common clinical features, laboratory findings, and pathogenetic theories are discussed