Thorough knowledge of the anatomical variations of the arterial pattern of the upper limb is of high clinical importance in many medical fields, from surgery to nursery and anesthesiologic practice. During a routine dissection at the Anatomy Department of the Medical University of Plovdiv, a rare variation of the vascular system in the upper limb of a study cadaver was observed. The exhibited variation was the occurrence of a brachioradial artery (BRA) that ran along the main axis of the arm, superficially to the median nerve. After dissection of the cubital fossa, an unusually underdeveloped radial artery was also spotted. Per our knowledge, such a type of duplicate radial artery, the coexistence of a BRA and an underdeveloped radial artery has not been reported in the relevant literature on the topic. The underdeveloped radial artery gave a major branch, the recurrent radial artery, a branch usually given by the brachial artery or the BRA in case of a BRA variation. Variations in the arterial pattern could potentially give insight into the features of the embryological development of the vascular system.

Targeted synergistic therapies represent a rapidly developing branch of oncology. The emergence of novel targeting agents allows for modulation of an ever-larger set of cellular pathways. The Unfolded Protein Response (UPR) is a key element of cellular proteostasis that is significantly hyperactivated in a wide range of cancer cell types, especially those with high secretory activity. As cancer cells are especially vulnerable to endoplasmic reticulum stress (ER Stress), they become heavily dependent on UPR function to maintain homeostasis. A wide number of pharmacologic agents can stimulate the UPR and shift it from its initial pro-survival phase to the terminal pro-apoptotic phase. Key strategies include the use of UPR feedback inhibitors (e.g., GRP78 antagonists), direct pathway inhibitors targeting the PERK or IRE1α branches, and signal pathway modulators (e.g., TKIs and BTK inhibitors) that indirectly exacerbate proteotoxic stress. In this study we provide a mechanistic framework where we classify synergistic therapies based on their mechanism of action and explore how they influence ER Stress and UPR activation. Evidence synthesized from these studies suggests that synergistic combinations can overcome therapeutic resistance and selectively induce apoptosis in cancer cells characterized by high proteotoxic stress.

Background/Objectives: Boronic acid-based proteasome inhibitors (BABPIs) including Bortezomib, Ixazomib, and Delanzomib are clinically relevant anticancer agents whose mechanism of action depends on direct interaction between the boronic acid warhead and the threonine residue at the first position (Thr1), leading to the formation of covalent tetrahedral complex. Although the formation of this complex is well studied, the subsequent behavior of the boronic acid warhead, particularly the possible formation of monoanionic boronate species through deprotonation of one of the two boronic hydroxyl groups, remains unexplored. Therefore, the present study addresses whether the formation of Thr1-OH and a monoanionic boronate species is thermodynamically favorable and which of the two hydroxyl groups is more favorable for deprotonation. Methods: Density Functional Theory (DFT) calculations at the B3LYP/6-311+G(d,p) level, combined with the Polarizable Continuum Model (PCM), were used to study two competing deprotonation pathways for the inhibitors and for a simplified warhead model. To mimic the proteasome environment, reactions were modeled in different polar media—diethyl ether (ε = 4), methanol (ε = 33), and water (ε = 78). Results: Our DFT calculations confirmed that the covalent tetrahedral complex could convert into Thr1-OH and a monoanionic boronate species, representing the deprotonation of one of the boronic hydroxyl groups. Deprotonation via pathway 1 is more favorable than deprotonation via pathway 2 for all inhibitors, especially in polar solvents. Bortezomib demonstrated a strong preference for -OH₁ deprotonation with ∆∆G ≈ −7 kcal·mol⁻¹. In contrast, Ixazomib, Delanzomib, and the simplified warhead model showed smaller ∆∆G values (≈−2 kcal·mol⁻¹), within the method’s uncertainty (±2 kcal·mol⁻¹), suggesting both deprotonation modes under physiological conditions. Conclusions: These results provide comparative thermodynamic insight into the deprotonation behavior of BABPIs, suggesting that the two hydroxyl groups are not equivalent during deprotonation. This finding offers a physicochemical framework that may support the rational design of next-generation BABPIs.