Antibody specificity against highly conserved membrane protein Claudin 6 driven by single atomic contact point.

The tight junction protein claudin 6 (CLDN6) is differentially expressed on cancer cells with almost no expression in healthy tissue. However, achieving therapeutic MAb specificity for this 4 transmembrane protein is challenging because it is nearly identical to the widely expressed CLDN9, with only 3 extracellular amino acids different. Most other CLDN6 MAbs, including those in clinical development are cross-reactive with CLDN9, and several trials have now been stopped. Here we isolated rare MAbs that bind CLDN6 with up to picomolar affinity and display minimal cross-reactivity with CLDN9, 22 other CLDN family members, or across the human membrane proteome. Amino acid-level epitope mapping distinguished the binding sites of our MAbs from existing clinical-stage MAbs. Atomic-level epitope mapping identified the structural mechanism by which our MAbs differentiate CLDN6 and CLDN9 through steric hindrance at a single molecular contact point, the γ carbon on CLDN6 residue Q156.

Effect of probiotics and gut microbiota on anti-cancer drugs: Mechanistic perspectives.

Bacteria present in probiotics, particularly the common Lactobacillus and Bifidobacterium microbes, have been found to induce anti-cancer action by enhancing cancer cell apoptosis and protecting against oxidative stress. Probiotics supplements also decrease the cancer-producing microorganism Fusobacterium. Studies have demonstrated that gut microbiota modifies the effect of chemo/radiation therapy. Gut microbes not only enhance the action of chemotherapy drugs but also reduce the side effects of these medications. Additionally, gut microbes reduce immunotherapy toxicity, in particular, the presence of Bacteroidetes or Bifidobacterium decreases the development of colitis by ipilimumab therapy. Probiotics supplements containing Bifidobacterium also reduce chemotherapy-induced mucositis and radiation-induced diarrhea. This review focused on elucidating the mechanism behind the anti-cancer action of Bifidobacterium species. Available studies have revealed Bifidobacterium species decrease cancer cell proliferation via the inhibition of growth factor signaling as well as inducing mitochondrial-mediated apoptosis. Moreover, Bifidobacterium species reduce the adverse effects of chemo/immuno/radiation therapy by inhibiting proinflammatory cytokines. Further clinical studies are needed to identify the powerful and suitable Bifidobacterium strain for the development of adjuvant therapy to support chemo/immuno/radiation therapy.

Flavonoids and Other Polyphenols Act as Epigenetic Modifiers in Breast Cancer.

Breast cancer is a common cancer that occurs due to different epigenetic alterations and genetic mutations. Various epidemiological studies have demonstrated an inverse correlation between breast cancer incidence and flavonoid intake. The anti-cancer action of flavonoids, a class of polyphenolic compounds that are present in plants, as secondary metabolites has been a major topic of research for many years. Our review analysis demonstrates that flavonoids exhibit anti-cancer activity against breast cancer occurring in different ethnic populations. Breast cancer subtype and menopausal status are the key factors in inducing the flavonoid's anti-cancer action in breast cancer. The dose is another key factor, with research showing that approximately 10 mg/day of isoflavones is required to inhibit breast cancer occurrence. In addition, flavonoids also influence the epigenetic machinery in breast cancer, with research demonstrating that epigallocatechin, genistein, and resveratrol all inhibited DNA methyltransferase and altered chromatin modification in breast cancer. These flavonoids can induce the expression of different tumor suppressor genes that may contribute to decreasing breast cancer progression and metastasis. Additional studies are required to confirm the contribution of epigenetic modifications by flavonoids to breast cancer prevention.

A novel HFO-based method for unsupervised localization of the seizure onset zone in drug-resistant epilepsy.

High frequency oscillations (HFOs) are potential biomarkers of epileptic areas. In patients with drug-resistant epilepsy, HFO rates tend to be higher in the seizure onset zone (SOZ) than in other brain regions and the resection of HFO-generating areas positively correlates with seizure-free surgery outcome. Nonetheless, the development of robust unsupervised HFO-based tools for SOZ localization remains challenging. Current approaches predict the SOZ by processing small samples of intracranial EEG (iEEG) data and applying patient-specific thresholds on the HFO rate. The HFO rate, though, varies largely over time with the patient's conditions (e.g., sleep versus wakefulness) and across patients. We propose a novel localization method for SOZ that uses a time-varying, HFO-based index to estimate the epileptic susceptibility of the iEEG channels. The method is insensitive to the average HFO rate across channels (which is both patient- and condition-specific), tracks the channel susceptibility over time, and predicts the SOZ based on the temporal evolution of the HFO rate. Tested on a preliminary dataset of continuous multi-day multichannel interictal iEEG recordings from two epileptic patients (117±97.6 h/per patient, mean ± S.D.), the reported SOZ prediction had an average 0.70±0.18 accuracy and 0.67±0.07 area under the ROC curve (mean ± S.D.) across patients.