Two granulysin (GRNLY) based immunotoxins were generated, one containing the scFv of the SM3 mAb (SM3GRNLY) and the other the scFv of the AR20.5 mAb (AR20.5GRNLY). These mAb recognize different amino acid sequences of aberrantly O-glycosilated MUC1, also known as the Tn antigen, expressed in a variety of tumor cell types. We first demonstrated the affinity of these immunotoxins for their antigen using surface plasmon resonance for the purified antigen and flow cytometry for the antigen expressed on the surface of living tumor cells. The induction of cell death of tumor cell lines of different origin positive for Tn antigen expression was stronger in the cases of the immunotoxins than that induced by GRNLY alone. The mechanism of cell death induced by the immunotoxins was studied, showing that the apoptotic component demonstrated previously for GRNLY was also present, but that cell death induced by the immunotoxins included also necroptotic and necrotic components. Finally, we demonstrated the in vivo tumor targeting by the immunotoxins after systemic injection using a xenograft model of the human pancreatic adenocarcinoma CAPAN-2 in athymic mice. While GRNLY alone did not have a therapeutic effect, SM3GRNLY and AR20.5GRNLY reduced tumor volume by 42 and 60%, respectively, compared with untreated tumor-bearing mice, although the results were not statistically significant in the case of AR20.5GRNLY. Histological studies of tumors obtained from treated mice demonstrated reduced cellularity, nuclear morphology compatible with apoptosis induction and active caspase-3 detection by immunohistochemistry. Overall, our results exemplify that these immunotoxins are potential drugs to treat Tn-expressing cancers.

According to published descriptions, one of the most incapacitating forms of orofacial pain is trigeminal neuralgia (TN). At its core, trigeminal neuropathic pain (TN) is still a clinical diagnostic that has to be differentiated from other forms of TN and face pain linked to other neuralgias or headache disorders. Imaging can only help with the cause of the pain, whether it’s a vascular origin or not. It is becoming more and more evident that there is no one-size-fits-all medication or surgical procedure that can effectively treat every patient with trigeminal neuralgia (TN). This is probably because TN is a diverse collection of conditions that all present with face discomfort. Medical therapy using anticonvulsants like carbamazepine is still the first-line treatment for TN. If this doesn't work for the patient, surgical treatments are available. Microvascular decompression is often a safe, efficient operation with results that are both rapid and long-lasting. Patients who may benefit from percutaneous techniques such as radiofrequency ablation, glycerol ablation, balloon compression, or a combination, include those who cannot undergo general anesthesia or whose medical conditions prohibit a suboccipital craniectomy. Radiosurgery may be a great option for patients with bleeding diathesis brought on by blood-thinning medications who are not eligible for invasive procedures or who do not want to undergo open surgical procedures, as long as the patient is aware that achieving maximum pain relief may take several months. In conclusion, peripheral neurectomies persist in offering a low-cost and resource-saving substitute for pain management to those residing in areas with restricted financial and healthcare resources. In the end, developing a better understanding of the molecular processes behind trigeminal neuralgia will lead to new, less intrusive, and more effective treatments.

Primary systemic treatment (PST) downsizes the tumor and improves pathological response. The aim of this study is to analyze the feasibility and tolerance of primary concurrent radio-chemotherapy (PCRT) in breast cancer patients. Patients with localized TN/HER2+ tumors were enrolled in this prospective study. Radiation is delivered concomitantly during the first 3 weeks of chemotherapy, and it is based on a 15 fractions scheme (40.5Gy/2.7Gy per fraction to whole breast and nodal levels I-IV. Chemotherapy is based on Pertuzumab-Trastuzumab-Paclitaxel followed by anthracyclines in HER2+ and CBDCA-Paclitaxel followed by anthracyclines in TN breast cancers patients. 58 patients were enrolled, 25 patients (43%) were TN and 33 patients HER2+ (57%). With a median follow-up of 24.2 months, 56 patients completed PCRT and surgery. A total of 35 patients (87.5%) achieved >90% loss of invasive carcinoma cell in the surgical specimen. The 70.8% and the 53.1% of patients with TN and HER-2+ subtype respectively achieved complete pathological response (pCR). This is the first study of concurrent neoadjuvant treatment in breast cancer in which three strategies are applied simultaneously: fractionation of RT in 15 sessions, adjustment of CT to tumor phenotype and local planning by PET. The pCR rates are encouraging.

The coevolution of species drives diversity in animals and plants and contributes to natural selection, whereas in host–parasite coevolution, a parasite may complete an incomplete evolutionary/developmental function by utilizing the host cell’s machinery. Analysis of related older data suggests that Plasmodium falciparum (P. falciparum), the pathogen of malaria tropica, cannot survive outside its human host because it is unable to perform the evolutionarily first protein glycosylation of serologically A-like, O-GalNAcα1-Ser/Thr-R, Tn antigen (“T nouvelle”) formation, owing to its inability for synthesizing the amino sugar N-acetyl-d-galactosamine (GalNAc). This parasite breaks the species barrier via hijacking the host's physiological A-like/Tn formation through abundantly expressing serine residues and creating hybrid A-like/Tn structures, which in the human blood group O(H) are attacked by the germline-encoded nonimmune polyreactive immunoglobulin M (IgM), exerting the highly anti-A/B/H-aggressive isoagglutinin activities. These activities physiologically undergo the ABO(H) blood group phenotype formation, occurring on the surfaces of red blood cells (RBC), epithelial and endothelial cells and on plasma proteins by identical glycosylation, performed by the ABO(H)-allelic glycotransferases, phenotypically downregulating the anti-A/B/H-reactive IgM (isoagglutinin) activities in the non-O blood groups. ABO(H) phenotype diversity, this way glycosidically linked and molecularly connected to humoral immunity, becomes exposed to the evolution.

While the angiotensin converting enzyme 2 (ACE2) protein is defined as the primary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, the viral serine molecule might be mobilized by the host's transmembrane protease serine subtype 2 (TMPRSS2) enzyme from the viral spike (S) protein and hijack the host’s N-acetyl-D-galactosamine (GalNAc) metabolism. The resulting hybrid, serologically A-like/Tn (T-nouvelle) structure potentially acts as a host–pathogen functional molecular bridge. In humans, this intermediate structure will hypothetically be replaced by ABO(H) blood group-specific, mucin-type structures, in the case of infection hybrid epitopes, implicating the phenotypically glycosidic accommodation of plasma proteins. The virus may, by mimicking the synthetic pathways of the ABO(H) blood groups, bind to the cell surfaces of the blood group O(H) by formation of a hybrid H-type antigen as the potential precursor of hybrid non-O blood groups, which does not affect the highly anti-glycan aggressive anti-A and anti-B isoagglutinin activities, exerted by the germline-encoded nonimmune immunoglobulin M (IgM). In the non-O blood groups, which have developed from the H-type antigen, these IgM activities are downregulated by phenotypic glycosylation, while adaptive immunoglobulins might arise in response to the hybrid A and B blood group structures, bonds between autologous carbohydrates and foreign peptides, suggesting the exertion of autoreactivity. The non-O blood groups thus become a preferred target for the virus, whereas blood group O(H) individuals, lacking the A/B phenotype-determining enzymes and binding the virus alone by hybrid H-type antigen formation, have the least molecular contact with the virus and maintain the critical anti-A and anti-B isoagglutinin activities, exerted by the ancestral IgM, which is considered the humoral spearhead of innate immunity.