Weakened APC/C activity at mitotic exit drives cancer vulnerability to KIF18A inhibition.

The efficacy of current antimitotic cancer drugs is limited by toxicity in highly proliferative healthy tissues. A cancer-specific dependency on the microtubule motor protein KIF18A therefore makes it an attractive therapeutic target. Not all cancers require KIF18A, however, and the determinants underlying this distinction remain unclear. Here, we show that KIF18A inhibition drives a modest and widespread increase in spindle assembly checkpoint (SAC) signaling from kinetochores which can result in lethal mitotic delays. Whether cells arrest in mitosis depends on the robustness of the metaphase-to-anaphase transition, and cells predisposed with weak basal anaphase-promoting complex/cyclosome (APC/C) activity and/or persistent SAC signaling through metaphase are uniquely sensitive to KIF18A inhibition. KIF18A-dependent cancer cells exhibit hallmarks of this SAC:APC/C imbalance, including a long metaphase-to-anaphase transition, and slow mitosis overall. Together, our data reveal vulnerabilities in the cell division apparatus of cancer cells that can be exploited for therapeutic benefit.

Antimicrobial Resistance and New Antimicrobial Agents, A Review of the Literature.

Antibiotic resistance has progressively diminished the effectiveness of conventional antibiotics, necessitating the cessation of clinical treatment. Consequently, novel antibacterial agents are urgently needed. We review studies on antimicrobial agents published during 2002-2023. Most of these studies were published within the last 10 years. By analyzing recent articles on antibiotic resistance and the development of new antibacterial drugs, we showed that although drug resistance is inevitable, the issue is being addressed gradually via the discovery and clinical application of antimicrobial peptides, nanomaterial drugs, and bacteriophage therapy. In light of the emergence of antimicrobial resistance, the development of new antimicrobial agents will require innovation in a field that has relied on traditional methods of discovery and development.

Centriole structural integrity defects are a crucial feature of Hydrolethalus Syndrome.

Hydrolethalus Syndrome (HLS) is a lethal, autosomal recessive ciliopathy caused by the mutation of the conserved centriole protein HYLS1. However, how HYLS1 facilitates the centriole-based templating of cilia is poorly understood. Here, we show that mice harboring the HYLS1 disease mutation die shortly after birth and exhibit developmental defects that recapitulate several manifestations of the human disease. These phenotypes arise from tissue-specific defects in cilia assembly and function caused by a loss of centriole integrity. We show that HYLS1 is recruited to the centriole by CEP120 and functions to recruit centriole inner scaffold proteins that stabilize the centriolar microtubule wall. The HLS mutation disrupts the interaction of HYLS1 with CEP120 leading to HYLS1 displacement and degeneration of the centriole distal end. We propose that tissue-specific defects in centriole integrity caused by the HYLS1 mutation prevent ciliogenesis and drive HLS phenotypes.

Gastric adenocarcinoma of the fundic gland type: A review of the literature.

Background and Aim: Gastric adenocarcinoma of the fundic gland type (GA-FG) is a newly described tumor entity but lacking consensus. This review summarizes the key features and controversies regarding this uncommon neoplasm. Methods: We reviewed studies on GA-FG published in English from 2007 to 2021. Results: We found that 327 cases (340 lesions) have been reported. GA-FG lesions originate from deep layers of the gastric mucosa, with the following characteristics on conventional white-light endoscopy examination. These lesions, macroscopically identified as submucosal tumor-like 0-IIa, tend to have a whitish discoloration without inflammation, atrophy, or intestinal metaplasia in the background mucosa. Tumors located in the upper third of the stomach are usually solitary, with an average size <10 mm. Contrastingly, magnifying endoscopy with narrow-band imaging mostly shows the absence of any demarcation line, with a regular microvascular pattern and regular microsurface pattern. GA-FGs are covered with normal foveolar epithelium, forming a so-called endless glands pattern in the deeper region, which are mainly composed of chief cells or parietal cells. Most tumors exhibit submucosal invasion, but lymphovascular invasion and nodal metastasis are rare. Regarding the treatment of GA-FG, endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) are effective treatment methods. Conclusions: GA-FG is a rare tumor that typically follows a benign course. This neoplasm has distinct endoscopic and pathological features and could be treated by ESD or EMR.