Signal transducers and activators of transcription (STATs) mediate essential signaling pathways in different biological processes, including immune responses, hematopoiesis, and neurogenesis. Among the STAT members, STAT3 plays crucial roles in cell proliferation, survival, and differentiation. While STAT3 activation is transient in physiological conditions, STAT3 becomes persistently activated in a high percentage of solid and hematopoietic malignancies (e.g., melanoma, multiple myeloma, breast, prostate, ovarian, and colon cancers), thus contributing to malignant transformation and progression. This makes STAT3 an attractive therapeutic target for cancers. Initial strategies aimed at inhibiting STAT3 functions have focused on blocking the action of its activating kinases or sequestering its DNA binding ability. More recently, the diffusion of proteomic-based techniques, which have allowed for the identification and characterization of novel STAT3-interacting proteins able to modulate STAT3 activity via its subcellular localization, interact with upstream kinases, and recruit transcriptional machinery, has raised the possibility to target such cofactors to specifically restrain STAT3 oncogenic functions. In this article, we summarize the available data about the function of STAT3 interactors in malignant cells and discuss their role as potential therapeutic targets for cancer treatment.

Introduction Besides distinctive respiratory and digestive hallmarks, COVID-19 has been recently associated with a high prevalence of pro-inflammatory and hypercoagulable states known as “COVID-19 Associated Coagulopathy” (CAC), corresponding to a worsening in patients’ conditions, whose causes are still to be elucidated. A link between anti-phospholipid antibodies (aPLs) and viral infections has long been suggested. APLs are assessed for anti-phospholipid syndrome (APS) diagnosis, characterized by thrombocytopenia, thrombosis, and coagulopathy. Furthermore, circulating immune complexes (CICs), arisen upon inflammatory responses and related immune dysregulation, can lead to endothelial cell damage and thrombotic complications. Method We performed an extended panel including IgG/IgM anti-cardiolipin, IgG/IgM anti-β2-glycoprotein-1, coupled with IgG/IgM anti-prothrombin, IgG/IgM anti-annexin-V on two COVID-19 patient groups (early and late infection time), and a negative control group. IgG CIC analysis followed to evaluate inflammatory status, through a possible complement system activation. Results Our results showed low positive case percentage in IgG/IgM anti-cardiolipin and IgG/IgM anti-β2-glycoprotein-1 assays (4.54%, 6.25%, and 4.55%; in early infection group, late infection group, and control group, respectively); few positive cases in IgG/IgM anti-prothrombin and IgG/IgM anti-annexin-V immunoassays; and no IgG CIC positivity in any patient. Conclusions In conclusion, our data show a low aPL prevalence, likely excluding an involvement in the pathogenesis of CAC. Interestingly, IgG/IgM anti-prothrombin and anti-annexin-V positive cases, detected in late infection group, suggest that aPLs could temporarily increase or could trigger a “COVID-19-induced-APS-like-syndrome” in predisposed patients. Key Points•To our knowledge, anti-prothrombin (aPT) antibodies, anti-annexin-V antibodies and CICs in COVID-19 patients have not been reported in the scientific literature.•Lack of uniformity and the low percentage of aCL/aβ2GP1 positivity preclude a putative role in CAC pathogenesis.•IgG/IgM anti-prothrombin and IgG/IgM anti-annexin-V data show that distribution of positive case number increases in late infection patients, significantly in anti-annexin-V results, suggesting a possible role for these anti-phospholipid antibodies in disease course.•aPLs can arise transiently in some patients with critical illness and SARS-CoV-2 infection (disappearing in a few weeks), as well as in other genetically predisposed patients; they could trigger a “COVID-19-induced-APS-like-syndrome”.

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Persistent activation of Signal Transducer and Activator of Transcription (STAT)3 occurs in a high percentage of tumors, including colorectal cancer (CRC), thereby contributing to malignant cell proliferation and survival. Although STAT3 is recognized as an attractive therapeutic target in CRC, conventional approaches aimed at inhibiting its functions have met with several limitations. Moreover, the factors that sustain hyper‐activation of STAT3 in CRC are not yet fully understood. The identification of tumor‐specific STAT3 cofactors may facilitate the development of compounds that interfere exclusively with STAT3 activity in cancer cells. Here, we show that progranulin, a STAT3 cofactor, is upregulated in human CRC as compared to nontumor tissue/cells and its expression correlates with STAT3 activation. Progranulin physically interacts with STAT3 in CRC cells, and its knockdown with a specific antisense oligonucleotide (ASO) inhibits STAT3 activation and restrains the expression of STAT3‐related oncogenic proteins, thus causing cell cycle arrest and apoptosis. Moreover, progranulin knockdown reduces STAT3 phosphorylation and cell proliferation induced by tumor‐infiltrating leukocyte (TIL)‐derived supernatants in CRC cell lines and human CRC explants. These findings indicate that CRC exhibits overexpression of progranulin, and suggest a role for this protein in amplifying the STAT3 pathway in CRC.

Introduction: Besides distinctive respiratory and digestive hallmarks, COVID-19 has been recently associated with a high prevalence of pro-inflammatory and hypercoagulable states known as “COVID-19 Associated Coagulopathy” (CAC), corresponding to a worsening in patients’ conditions, whose causes are still to be elucidated. A link between anti-phospholipids antibodies (aPLs) and viral infections has long been suggested. APLs are assessed for Anti-phospholipid Syndrome (APS) diagnosis, characterized by thrombocytopenia, thrombosis and coagulopathy. Furthermore, circulating immune complexes (CICs), arisen upon inflammatory responses and related immune dysregulation, can lead to endothelial cells damage and thrombotic complications.Method: We performed an extended panel including IgG/IgM anti-cardiolipin, IgG/IgM anti-β2-glycoprotein-1, coupled with IgG/IgM anti-prothrombin, IgG/IgM anti-annexin-V on two COVID-19 patient groups (early and late infection time) and a negative control group. IgG CICs analysis followed to evaluate inflammatory status, through a possible complement system activation.Results: Our results showed low positive cases percentage in IgG/IgM anti-cardiolipin and IgG/IgM anti-β2-glycoprotein-1 assays (4.54%, 6.25%, 4.55%; in early infection group, late infection group and control group, respectively); few positive cases in IgG/IgM anti-prothrombin and IgG/IgM anti-annexin-V immunoassays; no IgG CICs positivity in any patient.Conclusions: In conclusion, our data show a low aPLs prevalence, likely excluding an involvement in the pathogenesis of CAC.Interestingly, IgG/IgM anti-prothrombin and anti-annexin-V positive cases, detected in late infection group, suggest that aPLs could temporarily increase or could trigger a “COVID-19-induced-APS-like-syndrome” in predisposed patients.Finally, even though aPLs are transient, they may still have a thrombotic potential in genetically predisposed COVID-19 patients.

Defective expression of frataxin is responsible for the inherited, progressive degenerative disease Friedreich's Ataxia (FRDA). There is currently no effective approved treatment for FRDA and patients die prematurely. Defective frataxin expression causes critical metabolic changes, including redox imbalance and ATP deficiency. As these alterations are known to regulate the tyrosine kinase Src, we investigated whether Src might in turn affect frataxin expression. We found that frataxin can be phosphorylated by Src. Phosphorylation occurs primarily on Y118 and promotes frataxin ubiquitination, a signal for degradation. Accordingly, Src inhibitors induce accumulation of frataxin but are ineffective on a non-phosphorylatable frataxin-Y118F mutant. Importantly, all the Src inhibitors tested, some of them already in the clinic, increase frataxin expression and rescue the aconitase defect in frataxin-deficient cells derived from FRDA patients. Thus, Src inhibitors emerge as a new class of drugs able to promote frataxin accumulation, suggesting their possible use as therapeutics in FRDA.

Frataxin deficiency, responsible for Friedreich’s ataxia (FRDA), is crucial for cell survival since it critically affects viability of neurons, pancreatic beta cells and cardiomyocytes. In FRDA, the heart is frequently affected with typical manifestation of hypertrophic cardiomyopathy, which can progress to heart failure and cause premature death. A microarray analysis performed on FRDA patient’s lymphoblastoid cells stably reconstituted with frataxin, indicated HS-1-associated protein X-1 (HAX-1) as the most significantly upregulated transcript (FC = +2, P < 0.0006). quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) and western blot analysis performed on (I) HEK293 stably transfected with empty vector compared to wild-type frataxin and (II) lymphoblasts from FRDA patients show that low frataxin mRNA and protein expression correspond to reduced levels of HAX-1. Frataxin overexpression and silencing were also performed in the AC16 human cardiomyocyte cell line. HAX-1 protein levels are indeed regulated through frataxin modulation. Moreover, correlation between frataxin and HAX-1 was further evaluated in peripheral blood mononuclear cells (PBMCs) from FRDA patients and from non-related healthy controls. A regression model for frataxin which included HAX-1, group membership and group* HAX-1 interaction revealed that frataxin and HAX-1 are associated both at mRNA and protein levels. Additionally, a linked expression of FXN, HAX-1 and antioxidant defence proteins MnSOD and Nrf2 was observed both in PBMCs and AC16 cardiomyocytes. Our results suggest that HAX-1 could be considered as a potential biomarker of cardiac disease in FRDA and the evaluation of its expression might provide insights into its pathogenesis as well as improving risk stratification strategies.

Objective and design Fecal calprotectin (CLP) is widely known for its detection in stools of patients with inflammatory bowel diseases (IBDs), to investigate the intestinal inflammatory status. Current research is promoting the circulating protein role as a systemic inflammatory marker. However, most studies report serum calprotectin analysis although plasma assay prevents its massive release by granulocytes. In this perspective, the ongoing SARS-CoV-2 pandemic deserves deployment of convenient and easy-to-dose markers that could reliably address the state of infection. Methods We analyzed serum circulating calprotectin (cCLP) levels in hospitalized COVID-19 patients and plasma cCLP levels from patients with suspected SARS-CoV-2 infection, then assessed negative or positive on molecular tests. Results Our results confirm a significant circulating calprotectin increase in infected subjects respect to controls, in serum and plasma. Moreover, plasma calprotectin has higher levels in suspected patients with positive SARS-CoV-2-RT-PCR, compared to suspected patients with negative SARS-CoV-2-RT-PCR. Furthermore, ROC curves results showed the circulating plasma calprotectin discriminatory ability to differentiate infected SARS-CoV-2 patients at a cutoff value greater than 131.3 ng/ml. Conclusions Our data propose circulating calprotectin as a new, quantitative and predictive marker, which in addition to being an interesting generic inflammatory marker may provide important indications in SARS-CoV-2 infection.