Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly.

Cancer cells exhibit metabolic reprogramming and bioenergetic alteration, utilizing glucose fermentation for energy production, known as the Warburg effect. However, there are a lack of comprehensive reviews summarizing the metabolic reprogramming, bioenergetic alteration, and their oncogenetic links in gastrointestinal (GI) cancers. Furthermore, the efficacy and treatment potential of emerging anticancer drugs targeting these alterations in GI cancers require further evaluation. This review highlights the interplay between aerobic glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) in cancer cells, as well as hypotheses on the molecular mechanisms that trigger this alteration. The role of hypoxia-inducible transcription factors, tumor suppressors, and the oncogenetic link between hypoxia-related enzymes, bioenergetic changes, and GI cancer are also discussed. This review emphasizes the potential of targeting bioenergetic regulators for anti-cancer therapy, particularly for GI cancers. Emphasizing the potential of targeting bioenergetic regulators for GI cancer therapy, the review categorizes these regulators into aerobic glycolysis/ lactate biosynthesis/transportation and TCA cycle/coupled OXPHOS. We also detail various anti-cancer drugs and strategies that have produced pre-clinical and/or clinical evidence in treating GI cancers, as well as the challenges posed by these drugs. Here we highlight that understanding dysregulated cancer cell bioenergetics is critical for effective treatments, although the diverse metabolic patterns present challenges for targeted therapies. Further research is needed to comprehend the specific mechanisms of inhibiting bioenergetic enzymes, address side effects, and leverage high-throughput multi-omics and spatial omics to gain insights into cancer cell heterogeneity for targeted bioenergetic therapies.

Electrical cortical stimulation for refractory focal epilepsy: A long-term follow-up study.

OBJECTIVE: To report the long-term seizure control and safety of open-loop electrical cortical stimulation in patients with refractory focal epilepsy of diverse etiologies. METHODS: Six patients who received a therapeutic trial of cortical stimulation were included retrospectively. The frequency of seizures was recorded before and after implantation. Surgical procedure- and stimulation-related adverse effects were also recorded. RESULTS: The mean reductions in seizures were 61% at 1 year, 68% at 2 years, and 80% at 3-7 years post-implantation. The median follow-up time was 54 months (range 36-156 months). The etiologies of epilepsy included polymicrogyria in two patients, post-traumatic in one patient, and periventricular heterotopia, post-encephalitis, and familial lateral temporal lobe epilepsy in the remaining three patients. Status epilepticus stopped immediately after stimulation in three patients with focal status epilepticus or epilepsia partialis continua at baseline, with a long-term reduction in seizures of more than 90% and improvements in conscious level. Tissue incompatibility with the connection wire was noted in one patient, which subsided after the system was removed. CONCLUSIONS: Open-loop cortical stimulation of epileptic foci improved seizure control in our patients with refractory focal epilepsy of diverse etiologies. Electrical cortical stimulation stopped epilepsia partialis continua/focal status epilepticus immediately after the intervention and exhibited a sustained effect in reducing seizures. No procedure-related complications were observed. Further case cohort studies are needed to clarify which patients respond to open-loop cortical stimulation.

GALNT14 Genotype Predicts Postoperative Outcome of Stage III Colorectal Cancer With Oxaliplatin as Adjuvant Chemotherapy.

Adjuvant oxaliplatin-based chemotherapy is widely used for stage III colorectal cancer (CRC) after curative surgery. CRC is a molecularly heterogeneous disease, and our current knowledge of therapeutic response-related genetic factors remains limited. N-acetylgalactosaminyltransferase 14 (GALNT14)-rs9679162 genotype is a prognostic predictor for chemotherapy response in advanced hepatocellular carcinoma. Here, we investigated whether this genotype was related to the therapeutic outcome of stage III CRC.A cohort of 300 stage III CRC patients receiving curative resection followed by oxaliplatin-based chemotherapy was retrospectively recruited. GALNT14 genotypes and the clinicopathological factors were correlated with posttherapeutic prognosis.Of these patients, 18% patients had GALNT14-rs9679162 "TT" and 82% had the "GT" + "GG" genotypes. The analysis showed that the "TT" genotype was associated with unfavorable overall survival (OS, P = 0.009) but not with recurrence-free survival (RFS, P = 0.700). The subgroup analysis showed that the "TT" genotype was associated with unfavorable OS in the following subgroups: age ≤65 years, men, left side CRC, N2 stage, carcinoembryonic antigen >5 ng/mL, and mucinous histology (P = 0.012, 0.011, 0.009, 0.025, 0.013, and 0.007, respectively). Within the latter 2 subgroups, the "TT" genotype was the only independent predictor for OS. Finally, the "TT" genotype was associated with the T4 tumor stage (P = 0.017) and in patients with T4 tumors, the "TT" genotype was the only independent predictor for unfavorable RFS (P = 0.007).GALNT14 "TT" genotype was associated with unfavorable OS in stage III CRC patients receiving curative surgery and adjuvant oxaliplatin-based chemotherapy.

Duration of electroencephalographic recordings in patients with epilepsy.

PURPOSE: Previous studies have demonstrated different diagnostic yields with electroencephalography (EEG). Due to the small sample sizes or different patient populations (outpatients or inpatients only) in these previous studies, the clinical use of routine EEG and outpatient/inpatient video-EEG monitoring (VEM) needs further clarification. In this study, we investigated EEGs obtained from patients referred by epileptologists; by comparing the results of different EEG methods, we sought to determine the optimal durations and specific types of EEG recordings for different clinical situations. METHODS: The data from 335 routine EEGs, 281 3 h outpatient VEMs, and 247 inpatient VEMs (>48 h) were reviewed. We analyzed the latency to the first epileptiform discharge or clinical event. RESULTS: In patients undergoing outpatient VEMs, 48% of the first epileptiform discharges appeared within 20 min, and 64% appeared within 30 min. In patients undergoing inpatient VEMs, 21.2% had their first attack within 3h. The second peak of event occurrence was during the 33rd-36th h. Only 3.5% of the seizures were recorded after 57 h. The detection rate of epileptiform discharges was higher for 3h outpatient VEM than for routine EEG (54.1% versus 16.4%, p<0.01). Epileptic and/or nonepileptic events were recorded in 45.8% of the inpatient VEMs, the diagnostic yield of which was higher than for outpatient VEMs (p<0.01). Since the patients in this study had been selected to limit the bias between each group, the diagnostic yield of EEGs in this study are likely to have been higher than those found in routine practice. Patients with generalized epilepsy had a shorter latency to the first epileptiform discharge compared to patients with localization-related epilepsy (mean, 22.1 min versus 33.9 min, p<0.05). CONCLUSIONS: Two-thirds of epileptiform discharges were detected within 30 min of VEM. A 30-min recording is recommended for routine EEG examinations that aim to detect epileptiform discharges. A 3h outpatient VEM is a reasonable option when a routine EEG fails to detect epileptiform discharges. The latency to the first epileptiform discharge was shorter in patients with generalized epilepsy than in patients with localization-related epilepsy. 48 h of inpatient VEM might be adequate for detecting the target events.

Improved outcome after spinal cord compression injury in mice treated with docosahexaenoic acid.

In this study we have characterised the locomotor recovery, and temporal profile of cell loss, in a novel thoracic compression spinal cord injury (SCI) in the mouse. We have also shown that treatment with docosahexaenoic acid (DHA) is neuroprotective in this model of SCI, strengthening the growing literature demonstrating that omega-3 polyunsaturated fatty acids are neuroprotective after SCI. Compression SCI in C57BL/6 mice was produced by placing a 10 g weight for 5 min onto a 2 mm × 1.5 mm platform applied to the dura at vertebral level T12. Mice partly recovered from complete hindlimb paralysis and by 28 days post-surgery had plateaued at an average BMS locomotor score of 4.2, equivalent to weight support with plantar stepping. During the same period, neuronal loss at the epicentre increased from 26% of ventral horn neurons by day 1, to 68% by day 28. Delayed loss of oligodendrocytes was also seen (e.g. 84% by day 28 in the dorsal columns) and microglia/macrophage activation was maximal at 7 days. In contrast, axonal damage, judged by a decrease in the non-phosphorylated form of 200 kD neurofilament, was an early event, as the loss was seen by day 1 and did not change markedly over time. Mice that received an intravenous (i.v.) injection of 500 nmol/kg DHA 30 min after SCI, showed improved locomotor recovery and, at 28 day survival, reduced neuronal, oligodendrocyte and neurofilament loss, and reduced microglia/macrophage activation. For some of these indices of SCI, enrichment of the diet with 400 mg/kg/day DHA led to further improvement. However, dietary DHA supplementation, without the initial i.v. injection, was ineffective.

Transgenic mice with high endogenous omega-3 fatty acids are protected from spinal cord injury.

Omega-3 polyunsaturated fatty acids have been shown to have therapeutic potential in a variety of neurological disorders, including acute traumatic injury of the spinal cord. We addressed the question whether the neuroprotective effect of these compounds after spinal cord injury could also be seen when their level is raised in tissues prophylactically, prior to injury. In this study we used transgenic fat-1 mice to examine whether enriching spinal cord tissue in endogenous omega-3 polyunsaturated fatty acids has an effect on the outcome after compression spinal cord injury. The results demonstrate that after thoracic compression spinal cord injury, fat-1 mice display better locomotor recovery compared with the wild-type mice on a high omega-6 diet (high omega-6 polyunsaturated fatty acids in tissues), and wild-type mice on a normal diet (controls). This is associated with a significant increase in neuronal and oligodendrocyte survival and a decrease in non-phosphorylated neurofilament loss. The protection from spinal cord injury in fat-1 mice was also correlated with a reduction in microglia/macrophage activation and in pro-inflammatory mediators. In vitro experiments in dorsal root ganglia primary sensory neurons further demonstrated that a fat-1 tissue background confers robust neuroprotection against a combined mechanical stretch and hypoxic injury. In conclusion, our studies support the hypothesis that a raised omega-3 polyunsaturated fatty acid level and an altered tissue omega-6/omega-3 ratio prior to injury leads to a much improved outcome after spinal cord injury.

Improved outcome after peripheral nerve injury in mice with increased levels of endogenous ω-3 polyunsaturated fatty acids.

Functional recovery after a peripheral nerve injury (PNI) is often poor. There is a need for therapies that protect neurons against injury and enhance regeneration. ω-3 polyunsaturated fatty acids (PUFAs) have been shown to have therapeutic potential in a variety of neurological disorders, including acute traumatic injury. The objective of this study was to assess the neuroprotective and pro-regenerative potential of ω-3 PUFAs in PNI. We investigated this in mice that express the fat-1 gene encoding for ω-3 fatty acid desaturase, which leads to an increase in endogenous ω-3 PUFAs and a concomitant decrease in ω-6 PUFAs. Dorsal root ganglion (DRG) neurons from wild-type or fat-1 mice were subjected to a mechanical strain or hypoxic injury, and cell death was assessed using ethidium homodimer-1 labeling. The fat-1 background appears to confer robust neuroprotection against both injuries. We then examined the early functional and morphological changes in wild-type and fat-1 mice after a sciatic nerve crush. An accelerated functional recovery 7 d after injury was seen in fat-1 mice when assessed using von Frey filaments and the sciatic nerve functional index. These observations were also mapped to changes in injury-related markers. The injury-induced expression of ATF-3 was decreased in the DRG of fat-1 mice, whereas the axons detected 6 mm distal to the crush were increased. Fat-1 animals also had some protection against muscle atrophy after injury. In conclusion, both in vitro and in vivo experiments support the idea that a higher endogenous ω-3 PUFA could lead to beneficial effects after a PNI.

Long-term anterior thalamus stimulation for intractable epilepsy.

BACKGROUND: Deep brain stimulation (DBS) has re-emerged as an alternative therapy for intractable epilepsy. In this study, we investigated the feasibility, efficacy and safety of long-term anterior thalamic nucleus (ATN) stimulation for intractable epilepsy. METHODS: In this open-label pilot study of electrical stimulation of the ATN, we investigated four cases of intractable epilepsy (one man with generalized seizure, and three woman with partial seizure and secondary generalization; age range, 18-45 years), with a follow up of 2 years. Under the indication of bilateral or nonlocalized epileptic foci, each patient underwent stereotactic implantation of a quadripolar stimulating electrode in the bilateral ATN, guided by single-unit microelectrode recording. The stimulator was turned on after a sham period of 2-4 weeks. Seizure frequency was monitored and compared with the pre-implantation baseline. Twenty-one similar cases reported in the literature during the past 20 years were reviewed. RESULTS: Insertion into and stimulation through electrodes implanted in the ATN decreased seizure frequency, with a mean reduction rate of 49.6% in the current series. Two patients had seizure reductions of > or = 60%, with complete remission achieved in one patient. These findings were consistent with those in four other investigations of intractable epilepsy, which showed an overall rate of 45-55% in seizure reduction. One of our patients suffered a small frontal hemorrhage, and a second patient had extension erosion over the scalp; however, no resultant major or permanent neurological deficits were observed. CONCLUSIONS: Based on our study results and literature review, it appears reasonable to conclude that long-term ATN stimulation is a safe and effective treatment for seizure reduction in patients with intractable epilepsy.