Repolarisation of the immune-suppressive millieu of the ovarian tumour using targeted therapeutics

Ovarian cancer is a disease which is fatal in the majority of cases. The evolution of surgery and chemotherapy over the past 30 years has resulted in improvements in overall and progression-free survival. However, the rate of relapse in ovarian cancer is very high, suggesting that current treatment strategies are ineffective. Therefore, to overcome the poor prognosis of ovarian cancer, immunotherapeutic strategies have been devised such as the use of anti-CTLA-4 antibody therapy in melanoma. The principle that the immune system can effect either cancer development or clearance has been the subject of debate for over a century. Clinical results of novel immunotherapeutic approaches that aim to exploit and enhance this immunogenicity have had mixed successes such as IL-2 therapy in renal cell carcinoma. It is clear that whilst many tumours possess antigenic component in their make-up, they do not stimulate durable and effective immune responses in vivo. This may reflect the fact that tumours develop a network of escape mechanisms to circumvent tumour-specific immunity. Due to the ineffectual nature of current treatment options and the complexity of the tumour microenvironment a coherent stratagem needs to be composed. This thesis explores, in principle, a contemporary strategy to propagate an anti-tumour immune response within ovarian cancer by using existing drugs in combination to target three different facets of ovarian cancer immunity; Regulatory T cell (Treg) migration, poor release of the tumour associated antigen, MUC1, and reduced cytotoxic T cell (CTL) proliferation. The migration of Regulatory T cell (Treg) to ovarian cancer is principally mediated by the CCR4-CCL22 chemokine receptor-chemokine axis. AZ1, a specific antagonist for the chemokine receptor CCR4, which is highly expressed on Treg, abrogated the migration of these cells to the chemokine. This compound did not alter Treg function suggesting that its activity was specifically against Treg migration. In order to induce an adequate T cell response, sufficient antigen needs to be provided. Camptothecin, a classical topoisomerase inhibitor, demonstrated effective tumour cell death and release of the tumour-associated antigen, MUC1. The increase in tumour antigen release and decrease in tumour load was offset by significant immune toxicity. The incorporation of Camptothecin into a synthetic drug delivery system led to a decrease in immune toxicity while retaining the drug’s anti-tumour activity. Finally, in order to take advantage of tumour antigen release, it would be desirable to stimulate CTL. Imiquimod, the toll-like receptor 7 agonist, widely used in basal-cell carcinoma and melanoma was able to demonstrate a potential enhancement of an anti-tumour response in three ways. Firstly, the drug enhanced the activation and antigen uptake capacity of plasmacytoid dendritic cells. It also had a direct effect on CTL themselves whilst also reducing the suppressive effect of Treg. This thesis illustrates, in principle, the possibility that a poly-pharmaceutical approach can be taken to target ovarian cancer. It indicates that readily available compounds, when used in the correct combination, could be key in developing effective anti-cancer therapy. Future work in this area should focus on using existing chemotherapeutic and immunotherapeutic drugs in combination to illicit enhanced anti-tumour cytotoxicity. Critically, the next step in developing this strategy is to acquire suitable in vivo models. This is key as there is conflicting evidence regarding the efficacy of certain drugs in mice compared to man

Difficulty breathing or just a case of the nerves? Incidental finding of primary pleural schwannoma in a COVID-19 survivor

Schwannoma is a rare tumor that arises from the Schwann cells, which are specialized, myelin-producing cells of the peripheral nerve sheaths. As anatomic logic would dictate, these masses commonly occur in the skull base, cerebellopontine angle, and posterior spinal roots. Of this already rare entity, rarer still are the pleural schwannomas, representing approximately 1-2% of thoracic tumors. These tumors commonly affect adults with a propensity for the third and sixth decades of life and a comparative male predilection. Schwannomas are benign, indolent, and follow an asymptomatic course. As such, they often come to light incidentally.Here we report a case of primary pleural schwannomas in a 68-year-old female, found incidentally on a CT scan of the chest. To the best of our knowledge and literature review, no other similar case has been reported in our country, Pakistan. Around three weeks before her presentation, she was diagnosed with COVID-19. Her infection had run a mild course with quick recovery without the need for any hospitalization. Therefore, the manifestation of shortness of breath after resolution of all other symptoms prompted a further workup. Radiographic chest x-ray revealed an incidental finding of a large right upper lobe lung mass, slightly impinging on the trachea. This was followed by a chest CT scan at our radiological imaging facility, which showed a large, well-encapsulated, right upper lobe lung mass in the paraspinal apical location. She then underwent an image-guided biopsy of the aforementioned mass, pathological analysis of which was suggestive of a benign peripheral nerve sheath tumor (PNST) arising from the pleura (pleural schwannoma). She underwent right posterolateral thoracotomy with uneventful complete surgical removal of the pleural-based lung mass. Postoperative investigations included a chest x-ray that showed interval complete resection of the mass. Currently, she is asymptomatic and her clinical condition has improved with the successful resumption of her daily routine.Physicians thus need to keep pleural schwannomas in mind as a probable diagnosis of intrathoracic tumors. Indolent and asymptomatic, they are very amenable to surgical resection with little to no chances of recurrence in the long term. However, these patients should be closely followed with repeat imaging studies when symptomatic

Understanding unintentional childhood home injuries: pilot surveillance data from Karachi, Pakistan

<p>Abstract</p> <p>Background</p> <p>Childhood injuries, an important public health issue, globally affects more than 95% of children living in low-and middle-income countries. The objective of this study is to describe the epidemiology of childhood unintentional injuries in Karachi, Pakistan with a specific focus on those occurring within the home environment.</p> <p>Methods</p> <p>This was a secondary analysis of a childhood unintentional injury surveillance database setup in the emergency department of the Aga Khan Hospital, Karachi, Pakistan for 3 months. The data was collected by interviewing caretakers of children under 12 years of age presenting with an unintentional injury to the emergency departments of the four major tertiary care hospitals of Karachi, Pakistan.</p> <p>Results</p> <p>The surveillance included 566 injured children of which 409 (72%) injuries had taken place at/around home. Of 409 children, 66% were males and mostly between 5 and 11 years of age. Injuries commonly occurred during play time (51%). Fall (59%), dog bites (11%) and burns (9%) were the commonest mechanisms of injury. The majority of the children (78%) were directly discharged from the emergency room with predicted short term disability (42%). There were 2 deaths in the emergency department both due to falls.</p> <p>Conclusion</p> <p>Childhood injury surveillance system provides valuable in-depth information on child injuries. The majority of these unintentional childhood injuries occur at home; with falls, dog bites and burns being the most common types of unintentional childhood home injuries. Specific surveillance systems for child injuries can provide new and valuable information for countries like Pakistan.</p

Ethnomedicinal plants used against common digestive problems

Background: Ethnomedicinal knowledge is highly significant for persistence of human health care. Different studies have shown that medicinal plants are considered as curing agent for digestive disorders in Pakistan. The aim of present review is to explore this ethnomedicinal information all over the Pakistan and to investigate the ecological status of these species in the country.Methodology: Online literatures on ethnomedicinal plants used to treat digestive complaints in Pakistan were searched and gathered using online bibliographic databases including PubMed, Scopus, Google Scholar, Web of Science and Flora of Pakistan.Results: The review documented 178 medicinal plant species, belonging to 59 families, used for different digestive ailments. The majority of species were herbs (60%), used in drug preparation. The most frequent part used in preparation of these remedies is leaves (23%), followed by roots (19%).Conclusion: In conclusion, the study provides enormous ethno-medicinal knowledge and due to the unsustainable activities of the people of Pakistan, some medicinal plants need to be conserved for the future.Key words: Ethno-medicine, medicinal plants, gastrointestinal diseases, ecological status

Maximum Power Extraction from a Standalone Photo Voltaic System via Neuro-Adaptive Arbitrary Order Sliding Mode Control Strategy with High Gain Differentiation

In this work, a photovoltaic (PV) system integrated with a non-inverting DC-DC buck-boost converter to extract maximum power under varying environmental conditions such as irradiance and temperature is considered. In order to extract maximum power (via maximum power transfer theorem), a robust nonlinear arbitrary order sliding mode-based control is designed for tracking the desired reference, which is generated via feed forward neural networks (FFNN). The proposed control law utilizes some states of the system, which are estimated via the use of a high gain differentiator and a famous flatness property of nonlinear systems. This synthetic control strategy is named neuroadaptive arbitrary order sliding mode control (NAAOSMC). The overall closed-loop stability is discussed in detail and simulations are carried out in Simulink environment of MATLAB to endorse effectiveness of the developed synthetic control strategy. Finally, comparison of the developed controller with the backstepping controller is done, which ensures the performance in terms of maximum power extraction, steady-state error and more robustness against sudden variations in atmospheric conditions

Uncovering the burden of intentional injuries among children and adolescents in the emergency department

Introduction: In low- and middle-income countries, injuries are a leading cause of mortality in children. Much work has been done in the context of unintentional injuries but there is limited knowledge about intentional injuries among children. The objective of this paper was to understand the characteristics of children with intentional injuries presenting to emergency departments in Pakistan.Methods: The data was from the Pakistan National Emergency Departments Surveillance (Pak-NEDS), conducted from November 2010 to March 2011 in seven major emergency departments of Pakistan. Data on 30,937 children under 18 years of age was collected. This paper reports frequency of intentional injuries and compares patient demographics, nature of injury, and discharge outcome for two categories of intentional injuries: assault and self-inflicted injuries.Results:Intentional injuries presenting to the emergency departments (EDs) accounted for 8.2% (2551/30,937) amongst all other causes for under 18 years. The boy to girl ratio was 1:0.35. Intentional injuries included assault (n = 1679, 65.8%) and self-inflicted injuries (n = 872, 34.2%). Soft tissue injuries were most commonly seen in assault injuries in boys and girls but fractures were more common in self-inflicted injuries in both genders. Conclusion: Intentional injury is one of the reasons for seeking emergency treatment amongst children and a contributor to morbidity in EDs of Pakistan. Moreover, such injuries may be underestimated due to lack of reporting and investigative resources. Early identification may be the first step leading to prevention