Broad targeting of resistance to apoptosis in cancer

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer

Mirroring Opposition Threats

Hugo Chávez and his Bolivarian Movement came to power in 1999 promising to refound the Venezuelan state and restructure the polity in ways that would build “popular power” through the promotion of grassroots participation, organization, and mobilization. Once in office, the Bolivarian forces launched a series of initiatives to sponsor organization and mobilization among supporters, which ranged widely in their functions and strategic purpose. State-mobilized organizations can be seen as operating in three different arenas of politics: the local governance arena; the electoral arena; and the protest arena. From an ideological standpoint, the Bolivarian Movement was oriented toward sponsoring organizations that could operate in the first of these arenas, helping realize Chávez’s vision of constructing a “protagonistic democracy” by establishing vehicles for citizen participation in local governance. In the terminology of this volume, these activities are best seen as a form of “infrastructural mobilization,” working to solidify political support and achieve the government’s longer-term aims

Hemorrhage glioblastoma mimicks a dural-based meningioma

The so-called “dural tail sign” (DTS) is a thickening of the dura that is most often seen adjacent to a meningioma. Although the DTS is highly specific for meningioma, it has been observed in numerous other intracranial lesions. The origin of the DTS is an issue of debate. Some authors have described it as a tumor extension, while others have considered it as a proliferation of connective tissue, hypervascularity, and vascular dilatation within the dura and adjacent to cranial masses. Here, we reported a rare case of glioblastoma multiforme (GBM) with image findings of a DTS. A 74-year-old female was taken to our hospital due to the sudden onset of mental status change and right-side hemiparesis. Brain magnetic resonance imaging (MRI) with contrast enhancement showed an intracranial mass with heterogeneous enhancement in the left temporal lobe which was consistent with the DTS. A left frontotemporal craniotomy was performed, and grossly total tumor removal was achieved. The final pathology reported was GBM. Although it is rare, GBM may also on occasion be associated with a DTS. The histopathological examination for DTS in GBM is limited. Currently, excision of the dural tail in GBM is suggested

Comparison of the efficacy of esomeprazole and famotidine against stress ulcers in a neurosurgical intensive care unit

To compare the efficacy of esomeprazole and famotidine against stress ulcers and the association of these prophylactic agents with ventilator-associated pneumonia in patients admitted to neurosurgical intensive care unit (ICU). Sixty patients were randomly allocated into two groups (the esomeprazole and famotidine groups, n = 30 each) to receive prophylaxis medication for 7 days within 24 hours of admission in a neurosurgical ICU. Patients in the esomeprazole group received esomeprazole (40 mg) dissolved in water once a day through a nasogastric tube, whereas patients in the famotidine group received an intravenous infusion of famotidine (20 mg) every 12 hours. We then compared the occurrence of overt upper gastrointestinal bleeding and ventilator-associated pneumonia between these two groups. One patient in the famotidine group had overt upper gastrointestinal bleeding (3.3%), whereas the bleeding was not observed in patients in the esomeprazole group. Ventilator-associated pneumonia occurred in one patient (3.3%) from each group. One patient died within 30 days (3.3%) in the esomeprazole group and three patients (10%) died in the famotidine group. There was no difference in the occurrence of overt upper gastrointestinal bleeding (p = 1.000), ventilator-associated pneumonia (p = 1.000), and 30-day mortality (p = 0.612) between these two groups. In this small-scale study, the effect of administration of esomeprazole through a nasogastric tube on stress ulcer was similar to that of intravenous famotidine infusion in neurosurgical ICU patients. In addition, the association between prevalence of ventilator-associated pneumonia and administration of esomeprazole was also similar to that observed with famotidine infusion

Comparison of the efficacy of esomeprazole and famotidine against stress ulcers in a neurosurgical intensive care unit

Background: To compare the efficacy of esomeprazole and famotidine against stress ulcers and the association of these prophylactic agents with ventilator-associated pneumonia in patients admitted to neurosurgical intensive care unit (ICU). Patients and Methods: Sixty patients were randomly allocated into two groups (the esomeprazole and famotidine groups; n = 30 each) to receive prophylaxis medication for 7 days within 24 hours of admission in a neurosurgical ICU. Patients in the esomeprazole group received esomeprazole (40 mg) dissolved in water once a day through a nasogastric tube, whereas patients in the famotidine group received an intravenous infusion of famotidine (20 mg) every 12 hours. We then compared the occurrence of overt upper gastrointestinal bleeding and ventilator-associated pneumonia between these two groups. Results: One patient in the famotidine group had overt upper gastrointestinal bleeding (3.3%), whereas the bleeding was not observed in patients in the esomeprazole group. Ventilator-associated pneumonia occurred in one patient (3.3%) from each group. One patient died within 30 days (3.3%) in the esomeprazole group and three patients (10%) died in the famotidine group. There was no difference in the occurrence of overt upper gastrointestinal bleeding (p = 1.000), ventilator-associated pneumonia (p = 1.000), and 30-day mortality (p = 0.612) between these two groups. Conclusion: In this small-scale study, the effect of administration of esomeprazole through a nasogastric tube on stress ulcer was similar to that of intravenous famotidine infusion in neurosurgical ICU patients. In addition, the association between prevalence of ventilator-associated pneumonia and administration of esomeprazole was also similar to that observed with famotidine infusion

Intracranial pressure monitoring alone: Not an absolutely reliable tool after decompressive craniectomy for traumatic acute subdural hematoma

Introduction: The monitoring of intracranial pressure (ICP) in traumatic brain injury (TBI) is important for postoperative care. In our clinical practice, we have found that neurological deterioration because of contralateral epidural hematoma (EDH) occurs despite normal ICP in patients who have undergone decompressive craniectomy (DC). This study was performed to elucidate the dilemmas associated with ICP monitoring after DC and the possible complementary role of intraoperative and immediate postoperative imaging studies. Methods: Patients who had received DC due to TBI during a 7-year period were retrospectively identified from our database and evaluated. Logistic regression analyses were used to evaluate the associations between patients. Results: Twenty patients had contralateral skull fractures. Five patients (5 of 10, 50%) who developed EDH on the ipsilateral side of the skull fracture underwent operations for EDH evacuation due to the deterioration of their clinical condition. The ICP was significantly lower (P = 0.016) in these patients compared with patients who did not undergo secondary surgery due to EDH. Conclusions: ICP monitoring alone cannot absolutely ensure early detection of contralateral space-occupying lesion after DC due to improvement in cerebral compliance. Imaging studies using brain computed tomography is beneficial for early detection of delayed EDH after DC in a high-risk skull fracture with contralateral acute subdural hematoma patients

Dancers with non-specific low back pain have less lumbar movement smoothness than healthy dancers

Abstract Background Ballet is a highly technical and physically demanding dance form involving extensive end-range lumbar movements and emphasizing movement smoothness and gracefulness. A high prevalence of non-specific low back pain (LBP) is found in ballet dancers, which may lead to poor controlled movement and possible pain occurrence and reoccurrence. The power spectral entropy of time-series acceleration is a useful indicator of random uncertainty information, and a lower value indicates a greater smoothness or regularity. The current study thus applied a power spectral entropy method to analyze the movement smoothness in lumbar flexion and extension in healthy dancers and dancers with LBP, respectively. Method A total of 40 female ballet dancers (23 in the LBP group and 17 in the control group) were recruited in the study. Repetitive end-range lumbar flexion and extension tasks were performed and the kinematic data were collected using a motion capture system. The power spectral entropy of the time-series acceleration of the lumbar movements was calculated in the anterior–posterior (AP), medial–lateral (ML), vertical (VT), and three-directional (3D) vectors. The entropy data were then used to conduct receiver operating characteristic curve analyses to evaluate the overall distinguishing performance and thus cutoff value, sensitivity, specificity, and area under the curve (AUC) were calculated. Results The power spectral entropy was significantly higher in the LBP group than the control group in the 3D vector in both lumbar flexion and lumber extension (flexion: p = 0.005; extension: p < 0.001). In lumbar extension, the AUC in the 3D vector was 0.807. In other words, the entropy provides an 80.7% probability of distinguishing between the two groups (i.e., LBP and control) correctly. The optimal cutoff entropy value was 0.5806 and yielded a sensitivity of 75% and specificity of 73.3%. In lumbar flexion, the AUC in the 3D vector was 0.777, and hence the entropy provided a probability of 77.7% of distinguishing between the two groups correctly. The optimal cutoff value was 0.5649 and yielded a sensitivity of 90% and a specificity of 73.3%. Conclusions The LBP group showed significantly lower lumbar movement smoothness than the control group. The lumbar movement smoothness in the 3D vector had a high AUC and thus provided a high differentiating capacity between the two groups. It may therefore be potentially applied in clinical contexts to screen dancers with a high risk of LBP

The distribution of subarachnoid and intraventricular hemorrhage on computed tomography suggests the location of an idiosyncratic vascular lesion

The incidence of aneurysmal subarachnoid hemorrhage (SAH) associated with intraventricular hemorrhage (IVH) varies. In general, the anterior communicating artery and posterior circulation aneurysms cause such IVHs. A 48-year-old man visited the Neurosurgical Department for the evaluation of a severe thunderclap headache that had awakened him from sleep. Brain computed tomography revealed diffuse, but asymmetric, SAH. Digital subtraction cerebral angiography (DSA) showed multiple vascular lesions, including an obvious saccular aneurysm on the left anterior choroidal artery. After surgical clipping, rebleeding was noted, and repeat DSA demonstrated that the bleeding site was on the right posterior cerebral artery. The distribution of SAH associated with the preserved Liliequist membrane may suggest the origin of the bleeding. Treatment of the correct bleeding site is effective for preventing rebleeding

Oral fecal transplantation enriches Lachnospiraceae and butyrate to mitigate acute liver injury

Summary: While fecal microbiota transplantation (FMT) shows promise in treating human diseases, oral capsule FMT is more accepted and accessible to patients. However, microbe selection in the upper gastrointestinal tract (UGIT) through oral administration remains unclear. Here, we demonstrate that short-term oral fecal gavage (OFG) alleviates acetaminophen-induced acute liver injury (AILI) in mice, regardless of the divergent effects of commensal gut microbes. Pasteurized fecal gavage yields similar therapeutic effects. OFG enriches gut Lachnospiraceae and butyrate compared to donor feces. Butyrate mitigates AILI-induced ferroptosis via AMPK-ULK1-p62 signaling to simultaneously induce mitophagy and Nrf2 antioxidant responses. Combined N-acetylcysteine and butyrate administration significantly improves AILI mouse survival rates. These observations indicate the significance of the UGIT in modulating the implanted fecal microbes through oral administration and its potential biological and clinical impacts. Our findings also highlight a possible strategy for applying microbial metabolites to treat acute liver injury

Expression of inhibitors of apoptosis family protein in 7,12-dimethylbenz[a]anthracene-induced hamster buccal-pouch squamous-cell carcinogenesis is associated with mutant p53 accumulation and epigenetic changes

Fifty outbred Syrian golden hamsters were equally divided into three experimental groups and two control groups. The pouches of the experimental groups were painted bilaterally with a 0.5% 7,12-dimethylbenz[a]anthracene (DMBA) solution thrice a week for 3, 7 and 14 weeks. One of the control groups was applied with mineral oil while another control group remained untreated throughout the experiment. Neither survivin nor cIAP2 could be detected in any of the control tissues, whereas survivin and cIAP2 were found to be significantly increased in 3-, 7- and 14-week DMBA-treated pouches compared with the control pouches. Expression of XIAP, cIAP1 and NAIP were noted for both the control and 3-, 7- and 14-week DMBA-treated pouches, but levels were found to be significantly elevated in the experimental groups compared with the control pouches. p53 was not detected in any control tissues, but was significantly increased in 3-, 7- and 14-week DMBA-treated pouches. Direct sequencing revealed a point mutation (C→G) of p53 for pouch tissues treated with DMBA for 3 and 7 weeks, and there was a wide variation in the p53 sequence of the 14-week DMBA-treated pouch tissues, as compared with the control tissues. The control tissues had a survivin- and cIAP2-methylated allele, whereas the DMBA-treated tissues showed no evidence of survivin- and cIAP2-methylation. Neither the control nor DMBA-treated pouches showed evidence of XIAP-, cIAP1- or NAIP-methylation. Our results suggest that the expression of inhibitors of apoptosis family in DMBA-induced hamster buccal-pouch squamous-cell carcinogenesis may be modulated by both genetic (mutant p53) and epigenetic mechanisms