Glioblastoma with Both Oligodendroglioma and Primitive Neuroectodermal Tumor-Like Components in a Case with 9-Year Survival

Introduction. Glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults, is characterized by extensive heterogeneity in its clinicopathological presentation. A primary brain tumor with both astrocytic differentiation and neuronal immunophenotype features is rare. Here, we report a long-term survival patient who presented this rare form of GBM in the disease course. Presentation of Case. A 23-year-old woman, presenting with rapidly progressive headache and right-side weakness, was diagnosed with brain tumor over the left basal ganglion. She underwent the first craniectomy for tumor removal, and histopathology revealed classic GBM. Tumor recurrence occurred 8 years later. Another gross total resection was performed and pathology revealed GBM with the oligodendroglioma component (GBM-O). Due to disease progression, she received debulking surgery the following year. The third pathology revealed glioblastoma with primitive neuroectodermal tumor-like component (GBM-PNET). Discussion. GBM-PNETs are collision tumors with both neuronal and glial components. They are rare, and a few case reports have suggested that these tumors are associated with favorable outcomes but a higher risk of cerebrospinal fluid dissemination. Conclusion. We report a patient who developed the distinct pathologic variants of classic GBM, GBM-O, and GBM-PNET, throughout the disease course. Young age, aggressive surgical resection, and pathologic and genetic features may have contributed to the long-term survival of the patient

Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) is one of the major leading causes of cancer death worldwide due to the limited availability of biomarkers and therapeutic targets. Autophagy related protease 4B (ATG4B) is an essential protease for the autophagy machinery, and ATG4B phosphorylation at Ser383/392 increases its proteolytic activity. ATG4B expression and activation are crucial for cancer cell proliferation and invasion. However, the clinical relevance of ATG4B and phospho-Ser383/392-ATG4B for OSCC remains unknown, particularly in buccal mucosal SCC (BMSCC) and tongue SCC (TSCC). With a tissue microarray comprising specimens from 498 OSCC patients, including 179 BMSCC and 249 TSCC patients, we found that the protein levels of ATG4B and phospho-Ser383/392-ATG4B were elevated in the tumor tissues of BMSCC and TSCC compared with those in adjacent normal tissues. High protein levels of ATG4B were significantly associated with worse disease-specific survival (DSS) in OSCC patients, particularly in patients with tumors at advanced stages. In contrast, phospho-Ser383/392-ATG4B expression was correlated with poor disease-free survival (DFS) in TSCC patients. Moreover, ATG4B protein expression was positively correlated with phospho-Ser383/392-ATG4B expression in both BMSCC and TSCC. However, high coexpression levels of ATG4B and phospho-Ser383/392-ATG4B were associated with poor DFS only in TSCC patients, whereas they had no significant association with DSS in BMSCC and TSCC patients. In addition, silencing ATG4B with an antisense oligonucleotide (ASO) or small interfering RNA (siRNA) diminished cell proliferation of TW2.6 and SAS oral cancer cells. Further, knockdown of ATG4B reduced cell migration and invasion of oral cancer cells. Taken together, these findings suggest that ATG4B might be a biomarker for diagnosis/prognosis of OSCC and a potential therapeutic target for OSCC patients

Map1lc3b and Sqstm1 Modulated Autophagy for Tumorigenesis and Prognosis in Certain Subsites of Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) is one of the most common cancer types worldwide and can be divided into three major subsites: buccal mucosal SCC (BMSCC), tongue SCC (TSCC), and lip SCC (LSCC). The autophagy marker microtubule-associated protein light chain 3B (MAP1LC3B) and adaptor sequestosome 1(SQSTM1) are widely used proteins to evaluate autophagy in tumor tissues. However, the role of MAP1LC3B and SQSTM1 in OSCC is not fully understood, particularly in certain subsites. With a tissue microarray comprised of 498 OSCC patients, including 181 BMSCC, 244 TSCC, and 73 LSCC patients, we found that the expression levels of MAP1LC3B and cytoplasmic SQSTM1 were elevated in the tumor tissues of three subsites compared with those in adjacent normal tissues. MAP1LC3B was associated with a poor prognosis only in TSCC. SQSTM1 was associated with poor differentiation in three subsites, while the association with lymph node invasion was only observed in BMSCC. Interestingly, MAP1LC3B was positively correlated with SQSTM1 in the tumor tissues of BMSCC, whereas it showed no correlation with SQSTM1 in adjacent normal tissue. The coexpression of higher MAP1LC3B and SQSTM1 demonstrated a significantly worse disease-specific survival (DSS) and disease-free survival (DFS) in patients with BMSCC and LSCC, but not TSCC. The knockdown of MAP1LC3B and SQSTM1 reduced autophagy, cell proliferation, invasion and tumorspheres of BMSCC cells. Additionally, silencing both MAP1LC3B and SQSTM1 enhanced the cytotoxic effects of paclitaxel in the tumorspheres of BMSCC cells. Taken together, MAP1LC3B and SQSTM1 might modulate autophagy to facilitate tumorigenesis and chemoresistance in OSCC, particularly in BMSCC

Hypertension Accelerates Alzheimer’s Disease-Related Pathologies in Pigs and 3xTg Mice

Epidemiological studies suggest there is an association between midlife hypertension and increased risk of late-life Alzheimer’s disease (AD). However, whether hypertension accelerates the onset of AD or is a distinct disease that becomes more prevalent with age (comorbidity) remains unclear. This study aimed to test the possible relationship between hypertension and AD pathogenesis. Two animal models were used in this study. For the first model, 7-month-old Lanyu-miniature-pigs were given the abdominal aortic constriction operation to induce hypertension and their AD-related pathologies were assessed at 1, 2, and 3 months after the operation. The results showed that hypertension was detected since 1 month after the operation in the pigs. Levels of Aβ, amyloid precursor protein, RAGE, phosphorylated tau and activated GSK3β in the hippocampi increased at 3 months after the operation. For the second model, 3xTg mice at the ages of 2, 5, and 7 months were subjected to the “two-kidney-one-clip” operation to induce hypertension. One month after the operation, blood pressure was significantly increased in the 3xTg mice in any age. Aβ, amyloid plaque load, and phosphorylated tau levels increased in the operated mice. Furthermore, the operation also induced shrinkage in the dendritic arbor of hippocampal dentate gyrus granule neurons, leakage in the blood-brain barrier, activation in microglia, and impairment in the hippocampus-dependent learning and memory in the 3xTg mice. In conclusion, hypertension accelerates the onset of AD. Blood pressure control during midlife may delay the onset of AD

Image_2.PDF

<p>Epidemiological studies suggest there is an association between midlife hypertension and increased risk of late-life Alzheimer’s disease (AD). However, whether hypertension accelerates the onset of AD or is a distinct disease that becomes more prevalent with age (comorbidity) remains unclear. This study aimed to test the possible relationship between hypertension and AD pathogenesis. Two animal models were used in this study. For the first model, 7-month-old Lanyu-miniature-pigs were given the abdominal aortic constriction operation to induce hypertension and their AD-related pathologies were assessed at 1, 2, and 3 months after the operation. The results showed that hypertension was detected since 1 month after the operation in the pigs. Levels of Aβ, amyloid precursor protein, RAGE, phosphorylated tau and activated GSK3β in the hippocampi increased at 3 months after the operation. For the second model, 3xTg mice at the ages of 2, 5, and 7 months were subjected to the “two-kidney-one-clip” operation to induce hypertension. One month after the operation, blood pressure was significantly increased in the 3xTg mice in any age. Aβ, amyloid plaque load, and phosphorylated tau levels increased in the operated mice. Furthermore, the operation also induced shrinkage in the dendritic arbor of hippocampal dentate gyrus granule neurons, leakage in the blood-brain barrier, activation in microglia, and impairment in the hippocampus-dependent learning and memory in the 3xTg mice. In conclusion, hypertension accelerates the onset of AD. Blood pressure control during midlife may delay the onset of AD.</p

Image_3.PDF

<p>Epidemiological studies suggest there is an association between midlife hypertension and increased risk of late-life Alzheimer’s disease (AD). However, whether hypertension accelerates the onset of AD or is a distinct disease that becomes more prevalent with age (comorbidity) remains unclear. This study aimed to test the possible relationship between hypertension and AD pathogenesis. Two animal models were used in this study. For the first model, 7-month-old Lanyu-miniature-pigs were given the abdominal aortic constriction operation to induce hypertension and their AD-related pathologies were assessed at 1, 2, and 3 months after the operation. The results showed that hypertension was detected since 1 month after the operation in the pigs. Levels of Aβ, amyloid precursor protein, RAGE, phosphorylated tau and activated GSK3β in the hippocampi increased at 3 months after the operation. For the second model, 3xTg mice at the ages of 2, 5, and 7 months were subjected to the “two-kidney-one-clip” operation to induce hypertension. One month after the operation, blood pressure was significantly increased in the 3xTg mice in any age. Aβ, amyloid plaque load, and phosphorylated tau levels increased in the operated mice. Furthermore, the operation also induced shrinkage in the dendritic arbor of hippocampal dentate gyrus granule neurons, leakage in the blood-brain barrier, activation in microglia, and impairment in the hippocampus-dependent learning and memory in the 3xTg mice. In conclusion, hypertension accelerates the onset of AD. Blood pressure control during midlife may delay the onset of AD.</p

Image_1.PDF

<p>Epidemiological studies suggest there is an association between midlife hypertension and increased risk of late-life Alzheimer’s disease (AD). However, whether hypertension accelerates the onset of AD or is a distinct disease that becomes more prevalent with age (comorbidity) remains unclear. This study aimed to test the possible relationship between hypertension and AD pathogenesis. Two animal models were used in this study. For the first model, 7-month-old Lanyu-miniature-pigs were given the abdominal aortic constriction operation to induce hypertension and their AD-related pathologies were assessed at 1, 2, and 3 months after the operation. The results showed that hypertension was detected since 1 month after the operation in the pigs. Levels of Aβ, amyloid precursor protein, RAGE, phosphorylated tau and activated GSK3β in the hippocampi increased at 3 months after the operation. For the second model, 3xTg mice at the ages of 2, 5, and 7 months were subjected to the “two-kidney-one-clip” operation to induce hypertension. One month after the operation, blood pressure was significantly increased in the 3xTg mice in any age. Aβ, amyloid plaque load, and phosphorylated tau levels increased in the operated mice. Furthermore, the operation also induced shrinkage in the dendritic arbor of hippocampal dentate gyrus granule neurons, leakage in the blood-brain barrier, activation in microglia, and impairment in the hippocampus-dependent learning and memory in the 3xTg mice. In conclusion, hypertension accelerates the onset of AD. Blood pressure control during midlife may delay the onset of AD.</p