Daily new confirmed COVID-19 cases per million people - Nepal

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Bone Metastasis: Novel approaches to target its microenvironment !

Bone Metastasis

Various cancers can disseminate to the bone, including the most common malignancies in men and women, prostate and breast cancer, respectively. This article reviews the roles of the bone microenvironment in skeletal metastasis, highlighting the biology and clinical relevance of circulating tumour cells and disseminated tumour cells. Notably, bone metastases are associated with considerable morbidity and a poor prognosis, and the authors also discuss established and future therapeutic approaches for targeting components of the bone microenvironment to prevent or treat skeletal metastases.

Cancer is one of the leading causes of death worldwide. Despite medical progress in controlling primary tumours, resulting in prolonged survival, most patients with cancer will eventually develop metastatic disease and die from the associated complications. The two most common malignancies in women and men, breast cancer and prostate cancer, respectively, have been the subject of major therapeutic improvements with increasingly effective, rationally designed treatment options. These tumour types share a high propensity for bone metastasis. In autopsy studies from the era before mammography and prostate-specific antigen (PSA) screening, bone micrometastases from breast and prostate cancers were found to be more common than expected based on clinical findings, with 70–90% of patients having evidence of such metastases. In the current era, the majority of patients diagnosed with early stage breast or prostate cancer develop bone metastases after years of latency, or not at all; however, certain subgroups, such as men with castration-resistant prostate cancer (CRPC) and women with oestrogen receptor (ER), progesterone receptor and HER2 triple-positive breast cancer, have a high risk of developing bone metastases. Bone metastases typically constitute a ‘point of no return’, given that they are mostly incurable and are associated with fractures, pain, disability, reduced quality of life and a poor prognosis. Thus, the development of bone metastases marks a shift in treatment intent from cure to palliation, and thus increases the burden on both the individual and the health-care system.

The bone microenvironment is a distinct, highly dynamic compartment that hosts bona fide bone cells (osteoblasts, osteocytes, osteoclasts and their precursors), cells of the haematopoietic and immune systems, stromal cells, adipocytes, fibroblasts and endothelial cells, as well as an extracellular matrix (ECM) with large quantities of embedded growth and/or signalling factors. Functionally, these various populations of stem cells and mature cells interact to orchestrate bone remodelling, haematopoiesis and, thus, immune function during development, tissue regeneration and disease. For example, during osteogenic differentiation, mesenchymal skeletal stem cells (MSCs) and other osteoblast progenitors generate a high receptor activator of NF-κB ligand (RANKL) to osteoprotegerin (OPG) ratio to support osteoclast differentiation, whereas mature osteoblasts produce a lower, less osteoclastogenic ratio of these factors. Osteocytes, which are derived from osteoblasts, are not only the most abundant source of osteoclastogenic RANKL but also an exclusive source of the WNT signalling pathway antagonist sclerostin, which inhibits osteoblastogenesis from MSCs, thereby suppressing bone formation. These mutual interactions at the cellular and molecular levels ensure a dynamic balance between bone resorption and new bone formation and are, therefore, crucial determinants of bone health and disease, and specific alterations have been discovered in bone metastases, including activation of osteoclastic bone resorption, suppression of osteoblastic bone formation in osteolytic lesions, neoangiogenesis and aberrant osteoimmune interactions. In this context, tumour cells can exploit certain aspects of the bone microenvironment for homing, maintenance and expansive growth.

• Bone metastases are frequent events associated with advanced-stage malignancies, particularly breast and prostate cancers, and often result in pathological fractures, pain, disability, reduced quality of life and a poor prognosis.

• Circulating tumour cells can be detected in the blood using standardized liquid biopsy assays and can provide insights into the metastatic process, inform clinical risk stratification, and enable monitoring and tracing of resistance to therapy.

• Disseminated tumour cells (DTCs) can be detected in the bone marrow through bone marrow aspiration. Their fate is variable and can include apoptosis or immune-mediated cell death, persistence and dormancy, or progression to overt bone metastases.

• DTCs mutually interact with diverse components of the bone microenvironment, including bone cells, adipocytes, endothelial cells and various immune cells as well as the extracellular matrix. Survival strategies of DTCs involve interference with bone cell and adipocyte functions, immune evasion and neoangiogenesis.

• On the basis of emerging knowledge of the biology of bone metastasis, several bone-targeted therapies are currently under evaluation in preclinical studies and clinical trials.

• Approved therapies for patients with established bone metastases include bisphosphonates, the anti-receptor activator of NF-κB ligand (RANKL) antibody denosumab and radium-223.

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Mechanism how SARS-CoV-2 causes COVID-19 progression !

COVID-19:

"The viral receptor on human cells plays a critical role in disease progression !"

Viruses enter cells and initiate infection by binding to their cognate cell surface receptors. The expression and distribution of viral entry receptors therefore regulates their tropism, determining the tissues that are infected and thus disease pathogenesis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third human coronavirus known to co-opt the peptidase angiotensin-converting enzyme 2 (ACE2) for cell entry. The interaction between SARS-CoV-2 and ACE2 is critical to determining both tissue tropism and progression from early SARS-CoV-2 infection to severe coronavirus disease 2019 (COVID-19). Understanding the cellular basis of SARS-CoV-2 infection could reveal treatments that prevent the development of severe disease, and thus reduce mortality.

Key phases of disease progression

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin-converting enzyme 2 (ACE2). Initial infection of cells in the upper respiratory tract may be asymptomatic, but these patients can still transmit the virus. For those who develop symptoms, up to 90% will have pneumonitis, caused by infection of cells in the lower respiratory tract. Some of these patients will progress to severe disease, with disruption of the epithelial-endothelial barrier, and multi-organ involvement.

 

As with all coronaviruses, SARS-CoV-2 cell entry is dependent on its 180-kDa spike (S) protein, which mediates two essential events: binding to ACE2 by the amino-terminal region, and fusion of viral and cellular membranes through the carboxyl-terminal region. Infection of lung cells requires host proteolytic activation of spike at a polybasic furin cleavage site. To date, this cleavage site is found in all spike proteins from clinical SARS-CoV-2 isolates, as well as some other highly pathogenic viruses (e.g., avian influenza A), but it is absent from SARS-CoV and is likely to have been acquired by recombination between coronaviruses in bats. Cleavage by the furin protease therefore expands SARS-CoV-2 cell tropism and may have facilitated transmission from bats to humans. Membrane fusion also requires cleavage by additional proteases, particularly transmembrane protease serine 2 (TMPRSS2), a host cell surface protease that cleaves spike shortly after binding ACE2. SARS-CoV-2 tropism is therefore dependent on expression of cellular proteases, as well as ACE2.

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Coronavirus Disease (COVID-19) Outbreak Updates !

COVID-19:

This is how Covid-19 is spreading pandemic across the globe ! And with community transmission, Nepal is into the third stage of this pandemic !!

Watching carefully the entire video presents a very interesting and important hidden information how rapidly the virus at first spreads in China, then subsequently to other countries, at the same time how some countries including China were able to control and maintain the rate of spread while others such as Italy not able to and USA making to top !

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Laboratory Diagnosis of Coronavirus (COVID-19) - Rapid Diagnostic Test (RDT)!

COVID-19:

Laboratory methods for diagnosing COVID-19 follow two pathways:

1. Detection of the coronavirus itself, and
2. Detection of the body's adaptive immune response to the virus.

The stage of COVID-19 disease progression determines which detection method is most effective. The rapid diagnostic (RDT) test complements nucleic acid methods such as RT-PCR to improve speed of diagnosis and monitor disease progression. As the disease primarily attacks the lungs, specimens taken from the upper respiratory tract may be poor in quality and could lead to false-negatives with PCR.

To understand the clinical significance of results obtained from the RDT, the following information must be considered:

• The median incubation period is estimated to be 5.1 days.
• Specific IgM antibodies to SARS-CoV-2 become detectable 3-5 days after onset of symptoms.

Therefore, the RDT should not be used until symptoms have been present for at least 3 days.

Check HERE for RDT Details with VIDEO »

Watch the dynamic spread of the global pandemic COVID-19 !

COVID-19:

This is how Covid-19 is spreading pandemic across the globe !

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Watching carefully the entire video presents a very interesting and important hidden information how rapidly the virus at first spreads in China, then subsequently to other countries, at the same time how some countries including China were able to control and maintain the rate of spread while others such as Italy not able to and USA making to top !

WATCH VIDEO »

What are proteins and how much do you need?

Proteins:

Proteins are large molecules that our cells need to function properly. They consist of amino acids. The structure and function of our bodies depend on proteins. The regulation of the body's cells, tissues, and organs cannot happen without them.

Muscles, skin, bones, and other parts of the human body contain significant amounts of protein, including enzymes, hormones, and antibodies.

Proteins also work as neurotransmitters. Hemoglobin, a carrier of oxygen in the blood, is a protein.

What are proteins?

Proteins are long chains of amino acids that form the basis of all life. They are like machines that make all living things, whether viruses, bacteria, butterflies, jellyfish, plants, or human function.

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Hormonal Dysfunction in Male Infertility -Diagnosis and Treatment !

Male Infertility:

Treatment of infertility-related hormonal dysfunction in men requires an understanding of the hormonal basis of spermatogenesis. The best method for accurately determining male androgenization status remains elusive. Treatment of hormonal dysfunction can fall into two categories — empirical and targeted. Empirical therapy refers to experience-based treatment approaches in the absence of an identifiable etiology. Targeted therapy refers to the correction of a specific underlying hormonal abnormality.

Since the first case reports in 1910 of testicular atrophy after canine hypophysectomy, the hormonal basis of human reproduction has been an area of evolving investigation. An array of treatment modalities are available for hormonal dysfunction in the setting of male infertility, but the diagnosis of such dysfunction and its treatment is often empirical, or guided by the clinician's judgement, and can be open to interpretation. Our ability to understand the intra testicular hormonal environment and its effect on spermatogenesis is limited by current methods of routine clinical investigation.

Investigations into female infertility benefit from reliance on objective, verifiable outcomes such as ovulation, biochemical pregnancy, and clinical pregnancy. Meanwhile, the male counterpart has been hampered by the necessary dependence on bulk seminal parameters, which are notoriously poor predictors of fertility potential. Perhaps the only truly reliable semen analysis is one indicating azoospermia and that is where the most exciting clinical outcomes research has focused.

This review article describes and discusses the pathophysiology, diagnosis, and treatment of fertility-associated male hormonal dysfunction.

• Oestradiol is the principal mediator of negative feedback on the hypothalamic–pituitary axis, which illustrates the influence of selective oestrogen receptor modulators and aromatase inhibitors on male hormonal parameters

• Serum hormonal assays are unreliable indicators of intratesticular androgen levels, and the best approach for determining male androgen status remains elusive

• Follicle-stimulating hormone and inhibin B are markers of spermatogenesis and their relative values in the setting of an intact hypothalamic–pituitary–gonadal axis provide important information about testicular function

• Targeted hormonal therapy corrects specific hormonal dysfunctions, empirical hormonal therapy is employed when no underlying cause is identified and the evidence for empirical therapy is dependent on the type of medication used

• A return of sperm to the ejaculate or successful surgical sperm retrieval among men with azoospermia owing to spermatogenic dysfunction are the most objective indicators of outcomes of hormonal therapy

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