Cancer and Covid-19: Collectively catastrophic.

The Covid-19 pandemic has spread rapidly across the globe, resulting in more than 3 million deaths worldwide. The symptoms of Covid-19 are usually mild and non-specific, however in some cases patients may develop acute respiratory distress syndrome (ARDS) and systemic inflammation. Individuals with inflammatory or immunocompromising illnesses, such as cancer, are more susceptible to develop ARDS and have higher rates of mortality. This is mediated through an initial hyperstimulated immune response which results in elevated levels of pro-inflammatory cytokines and a subsequent cytokine storm. This potentiates positive feedback loops which are unable to be balanced by anti-inflammatory mediators. Therefore, elevated levels of IL-1ß, as a result of NLRP3 inflammasome activation, as well as IL-6 and TNF-α amongst many others, contribute to the progression of various cancer types. Furthermore, Covid-19 progression is associated with the depletion of CD8+ and CD4+ T cells, B cell and natural killer cell numbers. Collectively, a Covid-19-dependent pro-inflammatory profile and immune suppression promotes the optimal microenvironment for tumourigenesis, initiation and immune evasion of malignant cells, tumour progression and metastasis as well as cancer recurrence. There are, however, therapeutic windows of opportunity that may combat both Covid-19 and cancer to improve patient outcomes.

Molecular regulation of autophagy in a pro-inflammatory tumour microenvironment: New insight into the role of serum amyloid A.

Chronic inflammation, systemic or local, plays a vital role in tumour progression and metastasis. Dysregulation of key physiological processes such as autophagy elicit unfavourable immune responses to induce chronic inflammation. Cytokines, growth factors and acute phase proteins present in the tumour microenvironment regulate inflammatory responses and alter crosstalk between various signalling pathways involved in the progression of cancer. Serum amyloid A (SAA) is a key acute phase protein secreted by the liver during the acute phase response (APR) following infection or injury. However, cancer and cancer-associated cells produce SAA, which when present in high levels in the tumour microenvironment contributes to cancer initiation, progression and metastasis. SAA can activate several signalling pathways such as the PI3K and MAPK pathways, which are also known modulators of the intracellular degradation process, autophagy. Autophagy can be regarded as having a double edged sword effect in cancer. Its dysregulation can induce malignant transformation through metabolic stress which manifests as oxidative stress, endoplasmic reticulum (ER) stress and DNA damage. On the other hand, autophagy can promote cancer survival during metabolic stress, hypoxia and senescence. Autophagy has been utilised to promote the efficiency of chemotherapeutic agents and can either be inhibited or induced to improve treatment outcomes. This review aims to address the known mechanisms that regulate autophagy as well as illustrating the role of SAA in modulating these pathways and its clinical implications for cancer therapy.

Long-term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy.

BACKGROUND: In Phase 3 studies of ustekinumab, a fully human monoclonal IL-12/23p40 antibody approved for moderate-to-severe Crohn's disease, patients entered a long-term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM-UNITI maintenance are reported. METHODS: UNITI-1 (TNF-antagonist failures) and UNITI-2 (conventional therapy failures) patients (N = 1281) entered IM-UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose-adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8-32). All Week 44 completers could enter the long-term extension without further dose adjustment. Placebo patients discontinued following study unblinding. RESULTS: A total of 718 patients (all treated) entered the long-term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient-years) were similar among all placebo and ustekinumab patients (Week 0-96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed. CONCLUSIONS: Subcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

Signature biomarkers in Crohn's disease: toward a molecular classification.

In an effort to develop a molecular classification scheme for Crohn's disease (CD), mucosal biopsies from 69 CD patients and 28 normal controls were analyzed for expression of the RelA subunit of nuclear factor (NF)-kappaB, A20 (a negative regulator of NF-kappaB), polymeric immunoglobulin receptor (pIgR), tumor necrosis factor (TNF), and interleukin (IL)-8. Principal component analysis was used to classify individuals into three subsets based on patterns of biomarker expression. Set 1 included normal subjects and CD patients with mild disease and good responses to therapy, thus defining "normal" biomarker expression. CD patients in set 2, characterized by low expression of all five biomarkers, had moderate to severe disease and poor responses to immunosuppressive and anti-TNF therapy. Patients in set 3, characterized by low expression of RelA, A20, and pIgR, normal TNF and elevated IL-8, had acute inflammation that responded well to therapy. Classification of CD patients by these biomarkers may predict disease behavior and responses to therapy.

Defective macrophage function in neonates and its impact on unresponsiveness of neonates to polysaccharide antigens.

Neonates do not respond to thymus-independent (TI) antigens (Ag), making them vulnerable to infection with encapsulated bacteria. The antibody (Ab) response of adult and neonatal B cells to TI Ag requires certain cytokines, which are provided by T cells or macrophages (MPhi). Lipopolysaccharide (LPS) failed to induce neonatal MPhi to produce interleukin (IL)-1beta and tumor necrosis factor alpha (TNF-alpha) mRNA and to secrete IL-1beta, IL-12, and TNF-alpha. However, LPS induced neonates to secrete some IL-6 and three- to fivefold more IL-10 than adults. Accordingly, adding adult but not neonatal MPhi could restore the response of purified adult B cells to trinitrophenol (TNP)-LPS, a TI Ag. Increased IL-10 is causally related to decreased IL-1beta and IL-6 production, as IL-10(-/-) neonatal MPhi responded to LPS by secreting more IL-1beta and IL-6 than wild-type (WT) neonatal MPhi. When cultures were supplemented with a neutralizing Ab to IL-10, WT neonatal MPhi secreted increased amounts of IL-6 and allowed neonatal MPhi to promote adult B cells to mount an Ab response against TNP-LPS. Thus, neonates do not respond to TI Ag as a result of the inability of neonatal MPhi to secrete cytokines, such as IL-1beta and IL-6, probably as a result of an excess production of IL-10. This dysregulated cytokine secretion by neonatal MPhi may be a result of a reduction in expression of Toll-like receptor-2 (TLR-2) and TLR-4 and CD14.