Purpose: Human epidermal growth factor receptor 2 (HER2) is amplified or overexpressed in various malignancies, including breast and gastric cancers, and is associated with poor prognosis. Although HER2-targeted therapies, such as trastuzumab, improve outcomes in HER2-positive tumors, resistance often develops, and HER2-low tumors remain largely untargeted. Trastuzumab deruxtecan (T-DXd; DS-8201a) is a HER2-targeted antibody-drug conjugate with potent activity in HER2-positive and HER2-low tumors. This study evaluates its antitumor mechanisms and efficacy in HER2-positive, HER2-low, and homologous recombination deficiency (HRD)–associated models. Materials and Methods: Effects of T-DXd were assessed in cancer cell lines with diverse HER2 expression and HRD status. In vivo efficacy was evaluated using a xenograft model derived from HER2-low SNU-601 gastric cancer cells. Results: T-DXd reduced HER2 phosphorylation and downstream signaling (AKT, ERK) in HER2-positive cells. It induced DNA damage accumulation, as evidenced by increased γH2AX and p-Chk1 expression, and triggered apoptosis through cleaved poly(ADP-ribose) polymerase and caspase-3 activation, confirmed by annexin V staining. Similar effects were observed in HER2-low cells, with greater sensitivity in HRD cells. In xenografts, T-DXd reduced tumor volume by up to 80% at 4 mg/kg and 10 mg/kg. Histological analyses showed decreased Ki-67 and increased apoptosis. Furthermore, T-DXd induced G2/M cell cycle arrest and nuclear anaplasia, suggesting disruption of chromosomal stability as a potential antitumor mechanism. No significant toxicity, including body weight loss, was observed. Conclusion These findings highlight T-DXd’s effectiveness in HER2-low and HRD tumors, supporting its broader clinical application, including strategies targeting DNA damage repair pathways.

Purpose: Sustained cell proliferation and cell cycle acceleration in cancer cells inherently increase DNA damage, which interferes with homeostatic replication and transcription. Ataxia telangiectasia and Rad3-related (ATR) is crucial for initiation of the DNA damage response, and ATR inhibitors, such as elimusertib, induce increased replication stress and DNA damage. We investigated the anti-tumor effects of elimusertib and its mechanism of action in relation to replication stress. Materials and Methods: Anti-tumor effects were evaluated by MTT assay and colony formation assay in breast cancer cell lines in vitro, in breast cancer cell xenografts in vivo, and in patient-derived xenograft models. Cell cycle was assessed by flow cytometry and BrdU assay was used to measure replicating cells and S-phase progression. Alkaline and neutral comet assay was used to measure single and double-stranded DNA damages, respectively. Results: Elimusertib delayed S-phase progression in MDA-MB-453 and MDA-MB-231 cells and induced caspase-7–dependent apoptosis. Furthermore, the increase in sub-G1 population in the fluorescence-activated cell sorting analysis and Annexin V assay also confirmed apoptotic cell death. In the BrdU assay, single-stranded DNA (ssDNA) increased in sensitive cells and aberrant ssDNA induced DNA damage in S-phase and eventually caused replication catastrophe. Finally, these anti-tumor effects were proven in in vivo xenograft and patient-derived xenograft models. Conclusion Elimusertib had anti-tumor effects and induced replication catastrophe in breast cancer cells with a high replication rate. Moreover, cells under high DNA replication stress were sensitive to elimusertib. Further studies and treatment strategies with elimusertib are warranted for cancers with a high replication rate.

Potassium imbalances can be life-threatening and must be identified and corrected prior to surgery. Patients with hypokalemic periodic paralysis (hypoKPP) experience recurrent muscle weakness or paralysis due to hypokalemia. We present the management of a rare case of hypoKPP during surgery and discuss the general complications and perioperative management of the condition. A 70-year-old man with hypoKPP visited the emergency room with abdominal pain requiring a cholecystectomy. He had not experienced hypoKPP since 1993, 1 year after diagnosis. Preoperative examinations were normal, with a serum potassium level of 4.5 mEq/L. Surgery and recovery were uneventful, with potassium levels ≥ 3.3 mEq/L. The post-surgery serum potassium level was 4.3 mEq/L. The patient had no signs of hypokalemia until 1-week post-surgery. Thorough preoperative preparation, careful assessment of serum potassium levels, avoidance of triggering factors, and appropriate postoperative pain relief can help prevent a hypokalemic attack in patients with hypoKPP.

Potassium imbalances can be life-threatening and must be identified and corrected prior to surgery. Patients with hypokalemic periodic paralysis (hypoKPP) experience recurrent muscle weakness or paralysis due to hypokalemia. We present the management of a rare case of hypoKPP during surgery and discuss the general complications and perioperative management of the condition. A 70-year-old man with hypoKPP visited the emergency room with abdominal pain requiring a cholecystectomy. He had not experienced hypoKPP since 1993, 1 year after diagnosis. Preoperative examinations were normal, with a serum potassium level of 4.5 mEq/L. Surgery and recovery were uneventful, with potassium levels ≥ 3.3 mEq/L. The post-surgery serum potassium level was 4.3 mEq/L. The patient had no signs of hypokalemia until 1-week post-surgery. Thorough preoperative preparation, careful assessment of serum potassium levels, avoidance of triggering factors, and appropriate postoperative pain relief can help prevent a hypokalemic attack in patients with hypoKPP.

PURPOSE: Pim kinases are highly conserved serine/threonine kinases, and different expression patterns of each isoform (Pim-1, Pim-2, and Pim-3) have been observed in various types of human cancers, including gastric cancer. AZD1208 is a potent and selective inhibitor that affects all three isoforms of Pim. We investigated the effects of AZD1208 as a single agent and in combination with an Akt inhibitor in gastric cancer cells. MATERIALS AND METHODS: The antitumor activity of AZD1208 with/without an Akt inhibitor was evaluated in a large panel of gastric cancer cell lines through growth inhibition assays. The underlying mechanism was also examined by western blotting, immunofluorescence assay, and cell cycle analysis. RESULTS: AZD1208 treatment decreased gastric cancer cell proliferation rates and induced autophagy only in long-term culture systems. Light chain 3B (LC3B), a marker of autophagy, was increased in sensitive cells in a dose-dependent manner with AZD1208 treatment, which suggested that the growth inhibition effect of AZD1208 was achieved through autophagy, not apoptosis. Moreover, we found that cells damaged by Pim inhibition were repaired by activation of the DNA damage repair pathway, which promoted cell survival and led the cells to become resistant to AZD1208. We also confirmed that the combination of an Akt inhibitor with AZD1208 produced a highly synergistic effect in gastric cancer cell lines. CONCLUSION: Treatment with AZD1208 alone induced considerable cell death through autophagy in gastric cancer cells. Moreover, the combination of AZD1208 with an Akt inhibitor showed synergistic antitumor effects through regulation of the DNA damage repair pathway.
Apoptosis ; Autophagy ; Blotting, Western ; Cell Cycle ; Cell Death ; Cell Line ; Cell Proliferation ; Cell Survival ; DNA Damage ; Fluorescent Antibody Technique ; Humans ; Phosphotransferases ; Protein Isoforms ; Stomach Neoplasms

PURPOSE: The purpose of this study was to identify the influences of recognition on low fertility and views of marriage on childbirth will in university students. METHODS: Participants were 190 university students in Chungchungnamdo province, Korea. The data were collected from May to October 2018 and examined using descriptive statistics, t-test, analysis of variance, Pearson correlation and multiple regression with IBM SPSS Statistics ver. 24.0. RESULTS: Childbirth will was significantly correlated with recognition on low fertility (r=0.20, p=0.002) and views on marriage (r=0.53, p<0.001). Factors associated with childbirth will were views on marriage (β=0.24, p<0.001). CONCLUSION Theses results suggests that views on marriage have important influences on childbirth will in university students. To improve childbirth will, the positive views on marriage need to be formulated in university students.

PURPOSE: KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01 in vitro and in vivo. MATERIALS AND METHODS: The antitumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay. Wound healing and immunofluorescence assays were performed to evaluate the action mechanisms of KX-01. Changes in the cell cycle and molecular changes induced by KX-01 were also evaluated. A MDA-MB-231 mouse xenograft model was used to demonstrate the in vivo effects. RESULTS: KX-01 effectively inhibited the growth of breast cancer cell lines. The expression of phospho-Src and proliferative-signaling molecules were down-regulated in KX-01-sensitive TNBC cell lines. In addition, migration inhibition was observed by wound healing assay. KX-01-induced G2/M cell cycle arrest and increased the aneuploid cell population in KX-01-sensitive cell lines. Multi-nucleated cells were significantly increased after KX-01 treatment. Furthermore, KX-01 effectively delayed tumor growth in a MDA-MB-231 mouse xenograft model. CONCLUSION: KX-01 effectively inhibited cell growth and migration of TNBC cells. Moreover, this study demonstrated that KX-01 showed antitumor effects through the inhibition of Src signaling and the induction of mitotic catastrophe. The antitumor effects of KX-01 were also demonstrated in vivo using a mouse xenograft model.
Aneuploidy ; Animals ; Breast Neoplasms ; Cell Cycle ; Cell Cycle Checkpoints ; Cell Line ; Fluorescent Antibody Technique ; Heterografts ; In Vitro Techniques ; Mice ; Microtubules ; Mitosis* ; src-Family Kinases* ; Triple Negative Breast Neoplasms ; Tubulin ; Wound Healing

Locally advanced or metastatic disease accounts for two thirds of total patients with pancreatic cancer. Patients with pancreatic cancer are assessed as resectable, potentially resectable (borderline) or unresectable according to pre-operative examinations. The chances of resectability may be enhanced by using neoadjuvant systemic chemotherapy, radiotherapy or both. This case report presents a locally advanced pancreatic adenocarcinoma that was identified to be unresectable during surgical exploration. After receiving concurrent chemoradiotherapy, the patient was re-evaluated, identified as unresectable and received gemcitabine maintenance chemotherapy. Herein, we report the case of a patient with unresectable locally advanced pancreatic adenocarcinoma who achieved a complete response lasting for more than 32 months after receiving concurrent chmoradiotherapy followed by gemcitabine maintenance chemotherapy.
Adenocarcinoma ; Chemoradiotherapy ; Drug Therapy* ; Humans ; Maintenance Chemotherapy ; Pancreatic Neoplasms* ; Radiotherapy

Locally advanced or metastatic disease accounts for two thirds of total patients with pancreatic cancer. Patients with pancreatic cancer are assessed as resectable, potentially resectable (borderline) or unresectable according to pre-operative examinations. The chances of resectability may be enhanced by using neoadjuvant systemic chemotherapy, radiotherapy or both. This case report presents a locally advanced pancreatic adenocarcinoma that was identified to be unresectable during surgical exploration. After receiving concurrent chemoradiotherapy, the patient was re-evaluated, identified as unresectable and received gemcitabine maintenance chemotherapy. Herein, we report the case of a patient with unresectable locally advanced pancreatic adenocarcinoma who achieved a complete response lasting for more than 32 months after receiving concurrent chmoradiotherapy followed by gemcitabine maintenance chemotherapy.
Adenocarcinoma ; Chemoradiotherapy ; Drug Therapy* ; Humans ; Maintenance Chemotherapy ; Pancreatic Neoplasms* ; Radiotherapy