Chemotherapy reduces long-term quality of life in recurrence-free colon cancer survivors (LaTE study)-a nationwide inverse probability of treatment-weighted registry-based cohort study and survey.

AIM: Stage III colon cancer is routinely treated with adjuvant chemotherapy, which causes significant short-term morbidity. Its effect on long-term quality of life (QoL) is poorly investigated. The aim of this study was to investigate long-term QoL after curative treatment for colon cancer and explore the impact of chemotherapy on general and disease-specific QoL. METHOD: All patients aged under 75 years operated on for colon cancer between 30 September 2007 and 1 October 2019 were identified by the Cancer Registry of Norway. Exclusion criteria were distant metastasis, recurrence, dementia and rectal/rectosigmoid cancer operation. The primary outcome measure was Gastrointestinal Quality of Life Index (GIQLI). Secondary outcome measures included the Short Form Health Survey (SF-36). To achieve balanced groups when assessing differences in outcome measures the analyses were weighted by inverse probability weights based on a multiple logistic regression model with prechosen confounders. RESULTS: A total of 8627 patients were invited and 3109 responded (36% response rate). After exclusions 3025 patients were included, of whom 1148 (38%) had received adjuvant chemotherapy and 1877 (62%) had surgery alone, with mean follow-up of 75.5 versus 74.5 months, respectively. The GIQLI differed significantly between the groups [mean 111.0 (SD 18.4) vs. 115.6 (SD 17.8), respectively; mean difference: -4.6 (95% CI -5.9; -3.2); p < 0.001]. Those with the highest neurotoxicity exhibited the lowest GIQLI. The adjuvant chemotherapy group scored significantly lower in six of eight SF-36 domains compared with the surgery alone group. The main differences were found in social, physical and emotional function. CONCLUSION: Long-term QoL was significantly lower in patients who received adjuvant chemotherapy than in patients who did not. Neurotoxicity was closely related to reduced QoL in these patients. The low response rate limits the generalizability of the results.

Dietary restriction improves proteostasis and increases life span through endoplasmic reticulum hormesis.

Unfolded protein response (UPR) of the endoplasmic reticulum (UPRER) helps maintain proteostasis in the cell. The ability to mount an effective UPRER to external stress (iUPRER) decreases with age and is linked to the pathophysiology of multiple age-related disorders. Here, we show that a transient pharmacological ER stress, imposed early in development on Caenorhabditis elegans, enhances proteostasis, prevents iUPRER decline with age, and increases adult life span. Importantly, dietary restriction (DR), that has a conserved positive effect on life span, employs this mechanism of ER hormesis for longevity assurance. We found that only the IRE-1-XBP-1 branch of UPRER is required for the longevity effects, resulting in increased ER-associated degradation (ERAD) gene expression and degradation of ER resident proteins during DR. Further, both ER hormesis and DR protect against polyglutamine aggregation in an IRE-1-dependent manner. We show that the DR-specific FOXA transcription factor PHA-4 transcriptionally regulates the genes required for ER homeostasis and is required for ER preconditioning-induced life span extension. Finally, we show that ER hormesis improves proteostasis and viability in a mammalian cellular model of neurodegenerative disease. Together, our study identifies a mechanism by which DR offers its benefits and opens the possibility of using ER-targeted pharmacological interventions to mimic the prolongevity effects of DR.

Timing of TORC1 inhibition dictates Pol III involvement in Caenorhabditis elegans longevity.

Organismal growth and lifespan are inextricably linked. Target of Rapamycin (TOR) signalling regulates protein production for growth and development, but if reduced, extends lifespan across species. Reduction in the enzyme RNA polymerase III, which transcribes tRNAs and 5S rRNA, also extends longevity. Here, we identify a temporal genetic relationship between TOR and Pol III in Caenorhabditis elegans, showing that they collaborate to regulate progeny production and lifespan. Interestingly, the lifespan interaction between Pol III and TOR is only revealed when TOR signaling is reduced, specifically in adulthood, demonstrating the importance of timing to control TOR regulated developmental versus adult programs. In addition, we show that Pol III acts in C. elegans muscle to promote both longevity and healthspan and that reducing Pol III even in late adulthood is sufficient to extend lifespan. This demonstrates the importance of Pol III for lifespan and age-related health in adult C. elegans.

Can atherosclerosis be one of the causes of anterior spinal artery thrombosis?

A middle aged diabetic, hypertensive, dyslipidemic, heavy alcohol consumer man came with sudden onset upper back pain and quadriparesis. Examination showed upper motor type quadriparesis with sensation of pain loss up to level of C7 and totally spared proprioception. MRI spine showed features suggestive of anterior spinal artery stroke. Can atherosclerosis be a causative factor for spinal stroke?

Corrigendum: RNA Polymerase III, Ageing and Longevity.

[This corrects the article DOI: 10.3389/fgene.2021.705122.].

RNA Polymerase III, Ageing and Longevity.

Transcription in eukaryotic cells is performed by three RNA polymerases. RNA polymerase I synthesises most rRNAs, whilst RNA polymerase II transcribes all mRNAs and many non-coding RNAs. The largest of the three polymerases is RNA polymerase III (Pol III) which transcribes a variety of short non-coding RNAs including tRNAs and the 5S rRNA, in addition to other small RNAs such as snRNAs, snoRNAs, SINEs, 7SL RNA, Y RNA, and U6 spilceosomal RNA. Pol III-mediated transcription is highly dynamic and regulated in response to changes in cell growth, cell proliferation and stress. Pol III-generated transcripts are involved in a wide variety of cellular processes, including translation, genome and transcriptome regulation and RNA processing, with Pol III dys-regulation implicated in diseases including leukodystrophy, Alzheimer's, Fragile X-syndrome and various cancers. More recently, Pol III was identified as an evolutionarily conserved determinant of organismal lifespan acting downstream of mTORC1. Pol III inhibition extends lifespan in yeast, worms and flies, and in worms and flies acts from the intestine and intestinal stem cells respectively to achieve this. Intriguingly, Pol III activation achieved through impairment of its master repressor, Maf1, has also been shown to promote longevity in model organisms, including mice. In this review we introduce the Pol III transcription apparatus and review the current understanding of RNA Pol III's role in ageing and lifespan in different model organisms. We then discuss the potential of Pol III as a therapeutic target to improve age-related health in humans.

Stratification of Stage III colon cancer may identify a patient group not requiring adjuvant chemotherapy.

PURPOSE: Adjuvant chemotherapy for colon cancer with lymph node involvement (Stage III) has been the standard of care since the 1990s. Meanwhile, considerable evolvement of surgery combined with dedicated histopathological examinations may have led to stage migration. Furthermore, prognostic factors other than lymph node involvement have proven to affect overall survival. Thus, adjuvant chemotherapy in Stage III colon cancer should be reconsidered. The objective was to compare recurrence rates and survival in stage III colon cancer patients treated with or without adjuvant chemotherapy. Further, to assess the impact of extensive mesenterectomy, lymph node stage and vascular invasion on outcome. METHODS: Consecutive patients operated for Stage III colon carcinoma between 31 December 2005 and 31 December 2015 were identified in the pathological code register by matching colon (T67) and either adenocarcinoma (M81403) or mucinous adenocarcinoma (M84803), with lymph node (T08) and metastasis of adenocarcinoma (M81406 or M84806). Medical records of all identified patients were reviewed. RESULTS: Of 216 identified patients, 69 received no postoperative adjuvant chemotherapy (group NC), 69 insufficient adjuvant chemotherapy (FLV or < minimum recommended 6 cycles FLOX, group IC), and 78 sufficient adjuvant chemotherapy (≥ 6 cycles FLOX, group SC). When adjusted for age and comorbidity, 5-year overall survival did not differ statistically significant between groups (76% vs. 83% vs. 85%, respectively). Vascular invasion and a high lymph node ratio significantly reduced overall survival. CONCLUSION: The findings imply that subgroups of Stage III colon cancer patients have good prognosis also without adjuvant chemotherapy. For definite conclusions about necessity of adjuvant chemotherapy, prospective trials are needed.

Biological Effects of Aqueous Extract of Laurus noboilis L. Leaves on Some Histological and Immunological Parameters in Male Rat Liver Affected by Aluminum Chloride.

The present current study aimed to assess the protective effect of the aqueous extract of Laurus noboilis L. leaves against the toxic effects of aluminum chloride on liver tissue. A number of 36 male albino rats (Wistar) were randomly assigned to six groups (n=6) and treated for 30 days: Group 1 was regarded as the control group, Group 2 received Aluminum Chloride 90 mg/kg body weight orally by gavage, Group3: normal rats received aqueous extracts of Lurus Nobilis L. leaf 150 mg/kg body weight, Group 4: normal rats received aqueous extracts of Lurus Nobilis L. leaf 200 mg/kg body weight, Group 5: normal rats received aqueous extracts of Lurus Nobilis L. leaf 150 mg/kg body weight after a period of 4 h following treatment by Aluminum Chloride 90 mg/kg body weight, Group 6: normal rats received aqueous extracts of Laurus nobilis L. 200 mg /kg after a period of 4 h following treatment by Aluminum chloride with 90 mg/kg body weight. All the experimental animals were sacrificed, and sections of their liver were stained with Hematoxylin-Eosin for histological evaluations. Moreover, the liver enzymes and immune cytokines, such as Alkaline phosphatase (ALP), Alanine aminotransferase (ALT), and Aspartate aminotransferase (AST), tumor necrosis factor-alpha (TNF-alpha), and interleukin-10 (IL-10) were measured. As evidenced by the results of the current study, treatment with aqueous extract of Lurus Nobilis L. leaves at a dose of 150 and 200 mg/kg body weight orally contributed to the mitigation of the toxic effects of Aluminum Chloride in albino rats by reducing the damage and inflammation in the hepatocytes. The study suggested that the aqueous extract of Lurus Nobilis L. enhances the protective effect against liver toxicity.

Seizures with an atypical aetiology in an elderly patient: Eagle's syndrome--how does one treat it?

Onset of epilepsy can occur at any age, but it is relatively rare in the elderly. Late onset epilepsy is usually secondary to stroke, tumour, trauma or neurodegenerative disorders. A 62-year-old Indian woman presented with frequent drop attacks sometimes leading to unconsciousness and, rarely, associated with seizure. Her epilepsy work up was unremarkable. As the disease progressed, she was diagnosed as having idiopathic epilepsy, syncope or pseudo-seizure, on different occasions, and was treated at length with no response. Finally, detailed history-taking revealed her as having glossopharyngeal neuralgia leading to syncope and seizures. She subsequently improved. In clinical practice, such rare entities should also be considered for proper management of patients' ailments.

Role of lamotrigine augmentation in treatment-resistant obsessive compulsive disorder: a retrospective case review from South Asia.

BACKGROUND: Resistance to pharmacotherapy is one of the major challenges in the management of obsessive-compulsive disorder (OCD). OCD being a quite prevalent disorder, this resistance adds to the disability. Different strategies are being employed to counter this resistance, one of them being augmentation with glutamatergic modulators. Lamotrigine is being used for same since the recent past with mixed results. OBJECTIVE: The aim was to study the role of lamotrigine augmentation in serotonin reuptake inhibitor (SRI) resistant OCD patients. METHODOLOGY AND RESULTS: This study was carried by studying the case sheets of SRI resistant cases having already completed the treatment. A total of 22 cases sheets over 2 years met the study criteria with a mean age of mean age of 34.14 years. Over a period of 16 weeks, with a mean lamotrigine dose of 150 mg/day, 20 out of 22 patients had shown a significant response. The mean decrease in Yale-Brown Obsessive Compulsive Scale score was 67.23% with a baseline score of 28.87. There was a similar change on different domains of World Health Organization quality of life (P = 0.00564). CONCLUSION: Lamotrigine augmentation to on-going treatment with SRIs may be an effective move in case of SRI resistant OCD patients.

A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans.

Although dietary restriction (DR) is known to extend lifespan across species, from yeast to mammals, the signalling events downstream of food/nutrient perception are not well understood. In Caenorhabditis elegans, DR is typically attained either by using the eat-2 mutants that have reduced pharyngeal pumping leading to lower food intake or by feeding diluted bacterial food to the worms. In this study, we show that knocking down a mammalian MEKK3-like kinase gene, mekk-3 in C. elegans, initiates a process similar to DR without compromising food intake. This DR-like state results in upregulation of beta-oxidation genes through the nuclear hormone receptor NHR-49, a HNF-4 homolog, resulting in depletion of stored fat. This metabolic shift leads to low levels of reactive oxygen species (ROS), potent oxidizing agents that damage macromolecules. Increased beta-oxidation, in turn, induces the phase I and II xenobiotic detoxification genes, through PHA-4/FOXA, NHR-8 and aryl hydrocarbon receptor AHR-1, possibly to purge lipophilic endotoxins generated during fatty acid catabolism. The coupling of a metabolic shift with endotoxin detoxification results in extreme longevity following mekk-3 knock-down. Thus, MEKK-3 may function as an important nutrient sensor and signalling component within the organism that controls metabolism. Knocking down mekk-3 may signal an imminent nutrient crisis that results in initiation of a DR-like state, even when food is plentiful.

Can a stroke present with flexor spasms? A highly rare experience.

Involuntary movement disorders are not a common presentation of basal ganglia ischemia which may be induced by cerebral hemodynamic insufficiency. In secondary causes of movements disorders cerebrovascular diseases represent up to 22% and involuntary movements develop after 1-4% of strokes. We describe a case of a middle-aged woman who presented with intermittent involuntary tonic spasms or seizure-like episodes followed by weakness due to contralateral putaminal infarction. Initially thought to have Todd's paralysis she was not thrombolysed, but later she developed dense hemiplegia. Flexor spasms are generally thought to occur in lesions of the spinal cord but they can also occur in cerebral lesion, may be because of disinhibition of the spinal cord. Certain other theories also have been narrated, but this field still needs to be worked upon.