Epidemiology of Blackleg Disease in Ethiopia

Blackleg is an infectious bacterial disease of cattle and rarely of other ruminants. This bacteria is caused by Clostridium chauvoei which is an anaerobic, gram positive, motile, rod-shaped bacillus bacterium and persists in the soil as resistant spores. Blackleg is an acute or subacute but chronic disease may occur. It occurs most frequently in animals 6-24 months of age and the disease mainly affects none vaccinated as well as animals in good nutritional condition. It produces persistent spores when conditions are not ideal and spores are highly resistant to environmental factors and disinfectants. Infected ruminants do not directly transmit the disease to other animals. The bacteria enter the body through the alimentary mucosa after ingestion of contaminated feed. Secretion of cytolytic toxins that cause necrosis of vascular endothelia .The toxins are absorbed into the animal’s bloodstream which makes the animal acutely sick and causes rapid death. Economic importance due to blackleg is loss of animals, milk production and draft oxen, and cost for treatment and vaccination. Fatality rate of blackleg in fully susceptible populations approaches 100%. Clinical Signs include lethargy anorexia, reluctance to move lameness and recumbence. When superficial muscles are affected, swelling and crepitus are evident. Cattle found dead of blackleg are lying on the side with the affected hind limb stands out stiffly, bloating and putrefaction occur quickly and bloodstained from exudates, nostrils and anus. The disease can be diagnosed using laboratory diagnosis, Immune Fluorescent, Cell Culture and PCR. Control and prevention relies mainly on vaccination.

A cohort autopsy study defines COVID-19 systemic pathogenesis

Severe COVID-19 disease caused by SARS-CoV-2 is frequently accompanied by dysfunction of the lungs and extrapulmonary organs. However, the organotropism of SARS-CoV-2 and the port of virus entry for systemic dissemination remain largely unknown. We profiled 26 COVID-19 autopsy cases from four cohorts in Wuhan, China, and determined the systemic distribution of SARS-CoV-2. SARS-CoV-2 was detected in the lungs and multiple extrapulmonary organs of critically ill COVID-19 patients up to 67 days after symptom onset. Based on organotropism and pathological features of the patients, COVID-19 was divided into viral intrapulmonary and systemic subtypes. In patients with systemic viral distribution, SARS-CoV-2 was detected in monocytes, macrophages, and vascular endothelia at blood–air barrier, blood–testis barrier, and filtration barrier. Critically ill patients with long disease duration showed decreased pulmonary cell proliferation, reduced viral RNA, and marked fibrosis in the lungs. Permanent SARS-CoV-2 presence and tissue injuries in the lungs and extrapulmonary organs suggest direct viral invasion as a mechanism of pathogenicity in critically ill patients. SARS-CoV-2 may hijack monocytes, macrophages, and vascular endothelia at physiological barriers as the ports of entry for systemic dissemination. Our study thus delineates systemic pathological features of SARS-CoV-2 infection, which sheds light on the development of novel COVID-19 treatment.

Apatinib-Induced Hand–Foot Skin Reaction in Chinese Patients With Liver Cancer

Apatinib, an anti-tumor drug selectively targeting VEGFR2 (Vascular Endothelia Growth Factor Recpetor-2), has been proven effective in Chinese patients with liver cancer. Generally, treatment with apatinib achieves 16.1% of the overall objective remission rate (ORR) and 55.83% of the disease control rate (DCR) in Chinese patients with liver cancer. However, the prevalence of apatinib-induced hand–foot skin reaction (AI-HFSR) is noticeably high. The incidence of AI-HFSR is about 50.5%, of which Grades 1/2 and 3 are 38.8 and 11.6%, respectively. In addition, potential molecular mechanisms underlying the development of AI-HFSR are poorly understood and urgently needed to be investigated histologically. In this review, we summarize and review the current efficacy of apatinib and the prevalence of AI-HFSR in Chinese patients with liver cancer. Besides, we postulate the potential mechanisms underlying the development of AI-HFSR and discuss the optimal clinical management for this unwanted cutaneous side effect.

PODO447: a novel antibody to a tumor-restricted epitope on the cancer antigen podocalyxin

BackgroundThe success of new targeted cancer therapies has been dependent on the identification of tumor-specific antigens. Podocalyxin (Podxl) is upregulated on tumors with high metastatic index and its presence is associated with poor outcome, thus emerging as an important prognostic and theragnostic marker in several human cancers. Moreover, in human tumor xenograft models, Podxl expression promotes tumor growth and metastasis. Although a promising target for immunotherapy, the expression of Podxl on normal vascular endothelia and kidney podocytes could hamper efforts to therapeutically target this molecule. Since pathways regulating post-translational modifications are frequently perturbed in cancer cells, we sought to produce novel anti-Podxl antibodies (Abs) that selectively recognize tumor-restricted glycoepitopes on the extracellular mucin domain of Podxl.MethodsSplenic B cells were isolated from rabbits immunized with a Podxl-expressing human tumor cell line. Abs from these B cells were screened for potent reactivity to Podxl+ neoplastic cell lines but not Podxl+ primary endothelial cells. Transcripts encoding heavy and light chain variable regions from promising B cells were cloned and expressed as recombinant proteins. Tumor specificity was assessed using primary normal tissue and an ovarian cancer tissue microarray (TMA). Mapping of the tumor-restricted epitope was performed using enzyme-treated human tumor cell lines and a glycan array.ResultsOne mAb (PODO447) showed strong reactivity with a variety of Podxl+ tumor cell lines but not with normal primary human tissue including Podxl+ kidney podocytes and most vascular endothelia. Screening of an ovarian carcinoma TMA (219 cases) revealed PODO447 reactivity with the majority of tumors, including 65% of the high-grade serous histotype. Subsequent biochemical analyses determined that PODO447 reacts with a highly unusual terminal N-acetylgalactosamine beta-1 (GalNAcβ1) motif predominantly found on the Podxl protein core. Finally, Ab–drug conjugates showed specific efficacy in killing tumor cells in vitro.ConclusionsWe have generated a novel and exquisitely tumor-restricted mAb, PODO447, that recognizes a glycoepitope on Podxl expressed at high levels by a variety of tumors including the majority of life-threatening high-grade serous ovarian tumors. Thus, tumor-restricted PODO447 exhibits the appropriate specificity for further development as a targeted immunotherapy.

Angiostatic cues from the matrix: Endothelial cell autophagy meets hyaluronan biology

The extracellular matrix encompasses a reservoir of bioactive macromolecules that modulates a cornucopia of biological functions. A prominent body of work posits matrix constituents as master regulators of autophagy and angiogenesis and provides molecular insight into how these two processes are coordinated. Here, we review current understanding of the molecular mechanisms underlying hyaluronan and HAS2 regulation and the role of soluble proteoglycan in affecting autophagy and angiogenesis. Specifically, we assess the role of proteoglycan-evoked autophagy in regulating angiogenesis via the HAS2-hyaluronan axis and ATG9A, a novel HAS2 binding partner. We discuss extracellular hyaluronan biology and the post-transcriptional and post-translational modifications that regulate its main synthesizer, HAS2. We highlight the emerging group of proteoglycans that utilize outside-in signaling to modulate autophagy and angiogenesis in cancer microenvironments and thoroughly review the most up-to-date understanding of endorepellin signaling in vascular endothelia, providing insight into the temporal complexities involved.

A Na,K-ATPase–Fodrin–Actin Membrane Cytoskeleton Complex is Required for Endothelial Fenestra Biogenesis

Fenestrae are transcellular plasma membrane pores that mediate blood–tissue exchange in specialised vascular endothelia. The composition and biogenesis of the fenestra remain enigmatic. We isolated and characterised the protein composition of large patches of fenestrated plasma membrane, termed sieve plates. Loss-of-function experiments demonstrated that two components of the sieve plate, moesin and annexin II, were positive and negative regulators of fenestra formation, respectively. Biochemical analyses showed that moesin is involved in the formation of an actin–fodrin submembrane cytoskeleton that was essential for fenestra formation. The link between the fodrin cytoskeleton and the plasma membrane involved the fenestral pore protein PV-1 and Na,K-ATPase, which is a key regulator of signalling during fenestra formation both in vitro and in vivo. These findings provide a conceptual framework for fenestra biogenesis, linking the dynamic changes in plasma membrane remodelling to the formation of a submembrane cytoskeletal signalling complex.

The manifold roles of sialic acid for the biological functions of endothelial glycoproteins

Vascular endothelia are covered with a dense glycocalix that is heavily sialylated. Sialylation of vascular glycoconjugates is involved in the regulation of cell–cell interactions, be it among endothelial cells at cell junctions or between endothelial and blood-borne cells. It also plays important roles in modulating the binding of soluble ligands and the signaling by vascular receptors. Here, we provide an overview over the sialylation-function relationships of glycoproteins expressed in the blood and lymphatic vasculature. We first describe cellular interactions in which sialic acid contributes in a stereospecific manner to glycan epitopes recognized by glycan-binding proteins. Our major focus is however on the rarely discussed examples of vascular glycoproteins whose biological functions are modulated by sialylation through other mechanisms.

Role of NF-κB in Platelet Function

Platelets are megakaryocyte-derived fragments lacking nuclei and prepped to maintain primary hemostasis by initiating blood clots on injured vascular endothelia. Pathologically, platelets undergo the same physiological processes of activation, secretion, and aggregation yet with such pronouncedness that they orchestrate and make headway the progression of atherothrombotic diseases not only through clot formation but also via forcing a pro-inflammatory state. Indeed, nuclear factor-κB (NF-κB) is largely implicated in atherosclerosis and its pathological complication in atherothrombotic diseases due to its transcriptional role in maintaining pro-survival and pro-inflammatory states in vascular and blood cells. On the other hand, we know little on the functions of platelet NF-κB, which seems to function in other non-genomic ways to modulate atherothrombosis. Therein, this review will resemble a rich portfolio for NF-κB in platelets, specifically showing its implications at the levels of platelet survival and function. We will also share the knowledge thus far on the effects of active ingredients on NF-κB in general, as an extrapolative method to highlight the potential therapeutic targeting of NF-κB in coronary diseases. Finally, we will unzip a new horizon on a possible extra-platelet role of platelet NF-κB, which will better expand our knowledge on the etiology and pathophysiology of atherothrombosis.