Targeting colorectal cancer at the level of nuclear pore complex.

BACKGROUND: Nuclear pore complexes (NPCs) are the architectures entrenched in nuclear envelop of a cell that regulate the nucleo-cytoplasmic transportation of materials, such as proteins and RNAs for proper functioning of a cell. The appropriate localization of proteins and RNAs within the cell is essential for its normal functionality. For such a complex transportation of materials across the NPC, around 60 proteins are involved comprising nucleoporins, karyopherins and RAN system proteins that play a vital role in NPC's structure formation, cargo translocation across NPC, and cargoes' rapid directed transportation respectively. In various cancers, the structure and function of NPC is often exaggerated, following altered expressions of its nucleoporins and karyopherins, affecting other proteins of associated signaling pathways. Some inhibitors of karyopherins at present, have potential to regulate the altered level/expression of these karyopherin molecules. AIM OF REVIEW: This review summarizes the data from 1990 to 2023, mainly focusing on recent studies that illustrate the structure and function of NPC, the relationship and mechanisms of nucleoporins and karyopherins with colorectal cancer, as well as therapeutic values, in order to understand the pathology and underlying basis of colorectal cancer associated with NPC. This is the first review to our knowledge elucidating the detailed updated studies targeting colorectal cancer at NPC. The review also aims to target certain karyopherins, Nups and their possible inhibitors and activators molecules as a therapeutic strategy. KEY SCIENTIFIC CONCEPTS OF REVIEW: NPC structure provides understanding, how nucleoporins and karyopherins as key molecules are responsible for appropriate nucleocytoplasmic transportation. Many studies provide evidences, describing the role of disrupted nucleoporins and karyopherins not only in CRC but also in other non-hematological and hematological malignancies. At present, some inhibitors of karyopherins have therapeutic potential for CRC, however development of more potent inhibitors may provide more effective therapeutic strategies for CRC in near future.

Pakistan's HIV high-risk populations: Critical appraisal of failure to curtail spread beyond key populations.

Pakistan has been a hub of several HIV outbreaks over the last 2 decades, with four major outbreaks being registered since 2018. There has been a recent rise in HIV infections, especially in high-risk populations, mainly consisting of people who inject drugs, men who have sex with men, prisoners, the transgender women community, and female sex workers. Consistently poor infection control practices, unregulated unsafe blood transfusion, questionable ethical practices by healthcare providers, and a general lack of awareness are the main drivers of recent HIV outbreaks, with these issues exacerbated by the presence of untrained health care providers. To stop the spread of HIV systemically and sustainably, aggressive measures need to be taken at all levels by all concerned stakeholders that not only deal with building up testing, tracing, and treatment capabilities but also address underlying grassroots problems that have largely been ignored to date.

Pathways to prevention: insights on stemming HIV outbreaks in Larkana, Pakistan.

In the past two decades, Pakistan has faced multiple human immunodeficiency virus outbreaks, with Larkana appearing to be the hub of such outbreaks. While the previous Larkana outbreaks happened in high-risk populations, the alarming outbreak in 2019 occurred in a low-risk paediatric population, raising several concerning questions. Human immunodeficiency virus infections spilling into the general population is indicative of a steady increase in the number of cases, and the failure of control strategies to stem the concentrated epidemic from evolving. Although several causative factors have been identified from previous outbreaks, the one that occurred in 2019 may have been influenced by an additional, hitherto unexplored factor; child sexual abuse. The current narrative review was planned to summarise human immunodeficiency virus risk factors and causes identified in previous Larkana epidemics, to explore potential reasons for the outbreaks in children, and to discuss possible steps needed for stemming human immunodeficiency virus outbreaks in Pakistan.

Review of sepsis in Pakistan: how far have we come?

Pakistan is a low-middle-income country (LMIC) with a high burden of sepsis, yet there is a profound dearth of data regarding sepsis with no comprehensive review. In Pakistan, access to competent healthcare services is delayed and in places, often not available. Patients may present with sepsis after common community-acquired infections; the commonest sources of sepsis are the respiratory tract followed by the urinary tract. Gram-negative organisms are responsible for a large majority of cases of sepsis. Unfortunately, compliance with sepsis guidelines remains poor, and sepsis-related statistics do not seem to be improving significantly. Adult sepsis presents a significant burden on healthcare services, particularly in LMICs, and is a leading cause of morbidity and mortality. Many factors which affect outcomes and cost of care are amenable to prompt interventions. Consequently, there is a dire need to make concentrated efforts in implementing simple, cost-effective, and context-specific guidelines and monitoring strategies regarding the diagnosis and management of sepsis. The collection and analysis of information on sepsis in Pakistan hence remains imperative, in order to prospectively assess the effects of guideline compliance on outcomes and to formulate and refine new schemata to address emerging problems.

Hypertension as an Independent Risk Factor for In-Patient Mortality in Hospitalized COVID-19 Patients: A Multicenter Study.

Despite the lack of direct evidence that hypertension increases the likelihood of new infections, hypertension is known to be the most common comorbid condition in COVID-19 patients and also a major risk factor for severe COVID-19 infection. The literature review suggests that data is heterogeneous in terms of the association of hypertension with mortality. Hence, it remains a topic of interest whether hypertension is associated with COVID-19 disease severity and mortality. Herein, we perform a multicenter retrospective analysis to study hypertension as an independent risk for in-hospital mortality in hospitalized COVID-19 patients. This multicenter retrospective analysis included 515 COVID-19 patients hospitalized from March 1, 2020 to May 31, 2020. Patients were divided into two groups: hypertensive and normotensive. Demographic characteristics and laboratory data were collected, and in-hospital mortality was calculated in both groups. The overall mortality of the study population was 25.3% (130 of 514 patients) with 96 (73.8%) being hypertensive and 34 (26.2%) being normotensive (p-value of 0.01, statistically non-significant association). The mortality rate among the hypertensive was higher as compared to non-hypertensive; however, hypertensive patients were more likely to be old and have underlying comorbidities including obesity, diabetes mellitus, coronary artery disease, congestive heart failure, stroke, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and cancer. Therefore, multivariable logistic regression failed to show any significant association between hypertension and COVID-19 mortality. To our knowledge, few studies have shown an association between hypertension and COVID-19 mortality after adjusting confounding variables. Our study provides further evidence that hypertension is not an independent risk factor for in-hospital mortality when adjusted for other comorbidities in hospitalized COVID-19 patients.

SARS-CoV-2 induced coagulopathy and potential role of anticoagulation: Scoping review of literature.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can vary on a spectrum of asymptomatic disease to rarer manifestations like hypercoagulability especially among elderly patients admitted in the intensive care unit (ICU) and those with preexisting comorbidities. The exact mechanism behind this phenomenon is still unclear, however studies have shown an association with elevated cytokines and severe inflammatory response which encompasses this disease. Hypercoagulability can be limited to the lungs, or present as systemic manifestations of arterial and venous thrombosis leading to mortal outcomes. Thus, careful evaluation of risk factors should be performed by physicians and treatment with anticoagulants should be modified accordingly. All Coronavirus Disease 2019 (COVID-19) in-patients should receive thromboprophylactic therapy, with increased dosages administered to patients with increased disease severity or those with a high risk. D-dimer levels and sepsis-induced coagulopathy (SIC) score aid in identifying high risk patients and predicting outcome. This article highlights the pathophysiology behind hypercoagulability, its clinical associations and discusses therapeutic modalities to combat this fatal consequence of SARS-CoV-2.

Bone marrow necrosis and fat embolism syndrome in sickle cell disease during COVID-19 infection treated successfully with sequential red cell and plasma exchange.

Fat embolism syndrome (FES) is a rare life-threatening condition that is particularly seen in milder forms of sickle cell disease (SCD). Widespread systemic fat emboli are generated in the context of extensive bone marrow necrosis. Multi-organ failure with a high morbidity and mortality may quickly develop. Infection with Parvovirus B19 is a common precipitant. Here, the authors report the case of a 35-year-old Afro-Caribbean man with HbSC disease who presented with FES having tested positive for SARS-COV-2. He rapidly became critically ill and required admission to the intensive care unit for organ support. He was treated with red cell exchange and plasma exchange and made a good recovery to leave hospital at week 7.

Zinc-induced hypocupremia and pancytopenia, from zinc supplementation to its toxicity, a case report.

According to one estimate, zinc supplementation is widely used in the USA by almost 37% of the elderly population above age 71. Zinc has perceived benefits of immune system enhancement without realizing the harmful effects when used in excess. One of its under-recognized side effects is hypocupremia or copper deficiency due to excessive gastrointestinal losses as excessive zinc in the gut competes with copper for absorption. If severe, hypocupremia can cause hematologic changes (anemia, leukopenia/neutropenia, thrombocytopenia, and pancytopenia) with and without neurological deficits. Since zinc-induced hypocupremia is an overlooked entity, there is a lag of 12 months between the onset of symptoms and diagnosis. Most patients usually undergo a series of costly and sometimes invasive tests such as bone marrow biopsies during this lag time. Once diagnosed, the treatment is as simple as discontinuation of zinc and oral copper supplements. Here, we present a case report of zinc-induced hypocupremia and pancytopenia in an 81-year-old lady who was taking zinc supplements for macular degeneration. The patient presented with leukopenia with neutropenia, thrombocytopenia, and moderate anemia. This case report aims to educate clinicians since this is an easily missed entity and likely more prevalent than known due to widely used zinc supplementation.

Nanomedicine: A Promising Way to Manage Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating disease of the aging population characterized by the progressive and slow brain decay due to the formation of extracellular plaques in the hippocampus. AD cells encompass tangles of twisted strands of aggregated microtubule binding proteins surrounded by plaques. Delivering corresponding drugs in the brain to deal with these clinical pathologies, we face a naturally built strong, protective barrier between circulating blood and brain cells called the blood-brain barrier (BBB). Nanomedicines provide state-of-the-art alternative approaches to overcome the challenges in drug transport across the BBB. The current review presents the advances in the roles of nanomedicines in both the diagnosis and treatment of AD. We intend to provide an overview of how nanotechnology has revolutionized the approaches used to manage AD and highlight the current key bottlenecks and future perspective in this field. Furthermore, the emerging nanomedicines for managing brain diseases like AD could promote the booming growth of research and their clinical availability.