Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.

PURPOSE: Risk-reducing surgery for cancer prevention in solid tumors is a pressing clinical topic because of the increasing availability of germline genetic testing. We examined the short- and long-term outcomes of risk-reducing total gastrectomy (RRTG) and its lesser-known impacts on health-related quality of life (QOL) in individuals with hereditary diffuse gastric cancer syndrome. METHODS: Individuals who underwent RRTG as part of a single-institution natural history study of hereditary gastric cancers were examined. Clinicopathologic details, acute and chronic operative morbidity, and health-related QOL were assessed. Validated questionnaires were used to determine QOL scores and psycho-social-spiritual measures of healing. RESULTS: One hundred twenty-six individuals underwent RRTG because of a pathogenic or likely pathogenic germline CDH1 variant between October 2017 and December 2021. Most patients (87.3%; 110/126) had pT1aN0 gastric carcinoma with signet ring cell features on final pathology. Acute (<30 days) postoperative major morbidity was low (5.6%; 7/126) and nearly all patients (98.4%) lost weight after total gastrectomy. At 2 years after gastrectomy, 94% (64/68) of patients exhibited at least one chronic complication (ie, bile reflux, dysphagia, and micronutrient deficiency). Occupation change (23.5%), divorce (3%), and alcohol dependence (1.5%) were life-altering consequences attributed to total gastrectomy by some patients. In patients with a median follow-up of 24 months, QOL scores decreased at 1 month after gastrectomy and returned to baseline by 6-12 months. CONCLUSION: RRTG is associated with life-changing adverse events that should be discussed when counseling patients with CDH1 variants about gastric cancer prevention. The risks of cancer-prevention surgery should not only be judged in the context of likelihood of death due to disease if left untreated, but also based on the real consequences of organ removal.

Micronutrient Supplementation and Bone Health After Prophylactic Total Gastrectomy in Patients With CDH1 Variants.

INTRODUCTION: Patients with germline variants in CDH1 who undergo prophylactic total gastrectomy (TG) are at risk of altered nutrient and drug absorption due to modified gastrointestinal anatomy. Bone mineral density loss and micronutrient deficiencies have not been described previously in this patient population. METHODS: In this study we included 94 patients with germline CDH1 variants who underwent prophylactic TG between October 2017 and February 2022. We examined pre- and post-gastrectomy bone mineral density (BMD); serum biomarkers including calcium, phosphorus, alkaline phosphatase, and 25 (OH)-vitamin D; and postoperative adherence to calcium and multivitamin supplementation. RESULTS: Almost all patients (92/94, 98%) lost a substantial amount of weight post-TG, with an average weight loss of 26.5% at 12 months post-surgery. Serum biomarkers of mineral metabolism, namely calcium and phosphorus, did not change significantly after TG. However, average BMD was decreased in all patients at 12 months post-TG. Nonadherence to calcium supplementation was associated with a decrease in BMD. Nonadherence to multivitamin supplementation was associated with greater percent BMD loss in the femoral neck and total hip. CONCLUSIONS: Appropriate micronutrient supplementation and nutritional counseling pre- and postoperatively in patients undergoing prophylactic TG are important to mitigate the long-term effects of gastrectomy on bone health.

Emerging Adults Carrying a CDH1 Pathogenic or Likely Pathogenic Variant Face Diet and Lifestyle Challenges after Total Gastrectomy.

Emerging adults with a CDH1 pathogenetic or likely pathogenetic variant face a life-altering decision whether to undergo prophylactic total gastrectomy or to have frequent endoscopies for gastric cancer risk management. They are in a unique life stage with distinct characteristics, such as identity finding, career seeking, relationship exploring, establishing financial independence, and planning for or pursuing pregnancy. Research has shown that these emerging adults heavily weighed dietary and nutrition concerns after prophylactic total gastrectomy in their decision making for both timing of surgery and whether they should or should not undergo the surgery. These concerns are valid because of the significant dietary and lifestyle modifications that emerging adults need to commit to in order to prevent common sequelae after prophylactic total gastrectomy, which include early satiety, nausea, dumping syndrome, bile reflux, excessive weight loss, micronutrient deficiencies, and metabolic bone disorders. Therefore, working with a multidisciplinary team with expertise in CDH1 and hereditary diffuse gastric cancer, including a registered dietitian nutritionist, is essential for this population.

ONS Guidelines™ for Opioid-Induced and Non-Opioid-Related Cancer Constipation.

PURPOSE: This evidence-based guideline intends to support clinicians, patients, and others in decisions regarding the treatment of constipation in patients with cancer. METHODOLOGIC APPROACH: An interprofessional panel of healthcare professionals with patient representation prioritized clinical questions and patient outcomes for the management of cancer-related constipation. Systematic reviews of the literature were conducted. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to assess the evidence and make recommendations. FINDINGS: The panel agreed on 13 recommendations for the management of opioid-induced and non-opioid-related constipation in patients with cancer. IMPLICATIONS FOR NURSING: The panel conditionally recommended a bowel regimen in addition to lifestyle education as first-line treatment for constipation. For patients starting opioids, the panel suggests a bowel regimen as prophylaxis. Pharmaceutical interventions are available and recommended if a bowel regimen has failed. Acupuncture and electroacupuncture for non-opioid-related constipation are recommended in the context of a clinical trial. SUPPLEMENTARY MATERIAL CAN BE FOUND AT&NBSP;HTTPS: //bit.ly/30y29sI.

YO-001A, a new antifungal agent produced by Streptomyces sp. YO15-A001.

A new antifungal compound YO-001A was found from the culture broth of Streptomyces sp. YO15-A001, which was isolated from a soil sample collected in Toyama Prefecture. YO-001A was identified through morphological changes-based screening of the rice blast fungus, Pyricularia oryzae (P. oryzae). YO-001A is a new 26-membered macrolide of the oligomycin family, which exhibits potent antifungal activity against P. oryzae with an IC50 of 0.012 µM by disrupting mitochondrial respiration via inhibition of the FOF1-ATPase activity.

Ameliorative effects of selenium on arsenic-induced cytotoxicity in PC12 cells via modulating autophagy/apoptosis.

Arsenic is well known toxicant responsible for human diseases including cancers. On the other hand, selenium is an essential trace element with significant chemopreventive effects, anticancer potentials and antioxidant properties. Although previous studies have reported antagonism/synergism between arsenic and selenium in biological systems, the biomolecular mechanism/s is still inconclusive. Therefore, to elucidate the molecular phenomena in cellular level, we hypothesized that co-exposure of selenium with arsenic may have suppressive effects on arsenic-induced cytotoxicity. We found that selenium in co-exposure with arsenic increases cell viability, and suppresses oxidative stress induced by arsenic in PC12 cells. Consequently, DNA fragmentation due to arsenic exposure was also reduced by arsenic and selenium co-exposure. Furthermore, western blot analyses revealed that simultaneous exposure of both metals significantly inhibited autophagy which further suppressed apoptosis through positively regulation of key proteins; p-mTOR, p-Akt, p-Foxo1A, p62, and expression of ubiquitin, Bax, Bcl2, NFкB, and caspases 3 and 9, although those are negatively regulated by arsenic. In addition, reverse transcriptase PCR analysis confirmed the involvement of caspase cascade in cell death process induced by arsenic and subsequent inhibition by co-exposure of selenium with arsenic. The cellular accumulation study of arsenic in presence/absence of selenium via inductively coupled plasma mass spectrometry confirmed that selenium effectively retarded the uptake of arsenic in PC12 cells. Finally, these findings imply that selenium is capable to modulate arsenic-induced intrinsic apoptosis pathway via enhancement of mTOR/Akt autophagy signaling pathway through employing antioxidant potentials and through inhibiting the cellular accumulation of arsenic in PC12 cells.

Melinjo (Gnetum gnemon) Seed Extract Consumption during Lactation Improved Vasodilation and Attenuated the Development of Hypertension in Female Offspring of Fructose-Fed Pregnant Rats.

BACKGROUND: Fructose intake has been correlated with increased prevalence of metabolic disorders including hypertension. In pregnant rats, fructose intake has been reported to have adverse effects on the health of its offspring. This study investigated the effects of gestational maternal fructose consumption and if supplementation with melinjo seed extracts to the maternal diet during lactation could benefit the offspring in later life. METHODS: Pregnant rats were randomly divided into three groups: untreated (CC), fructose-treated (FC), and fructose and melinjo-treated (FM). FC and FM groups received 100 g/L of D(-)-fructose solution by means of the drinking water during gestation while CC received normal drinking water. During lactation, CC and FC groups were given standard commercial laboratory diet, while the FM group was given commercial laboratory diet with 0.1% melinjo seed extracts. After weaning, the offspring were given normal drinking water and standard commercial diet until week 17. The blood pressure of the offspring was monitored until the 16th week. During week 17, the offspring were killed, and the kidneys were collected and analyzed. RESULTS: The level of renal phosphorylated AMP-activated protein kinase (pAMPK) in FM of 17-week female offspring was significantly higher compared with FC and CC groups. Maternal fructose intake down-regulated the renal endothelial isoform of nitric oxide synthetase expression in FC and maternal melinjo seed extract consumption maintained renal endothelial isoform of nitric oxide synthetase expression in FM of 17-week female offspring. In addition, maternal melinjo seed extract intake during lactation lowered the systolic blood pressure in FM of 17-week female offspring. CONCLUSION: Female offspring were more vulnerable to the effects of placental fructose and melinjo seed extracts, suggesting sex-specific sensitivities. In summary, our data show that melinjo seed extract consumption during lactation improved vasodilation and attenuated the development of hypertension in the 17-week female offspring of fructose-fed pregnant rats. Birth Defects Research 110:27-34, 2018. © 2017 Wiley Periodicals, Inc.

Myricetin enhances on apoptosis induced by serum deprivation in PC12 cells mediated by mitochondrial signaling pathway.

Polyphenols have many beneficial effects and an effective disease therapeutic auxiliary drug. Previously, myricetin, a polyphenol, had been reported to possess various biological effects on human physiology. However, mechanism of myricetin on apoptosis induced in PC12 cells is still unclear. PC12 cells were treated with myricetin in two concentration levels comprising 0.1 and 1 µM under serum-free condition. As a result, morphological changes were observed using trypan blue assay. DNA fragmentation was determined by DNA ladder assay to evaluate DNA damage levels. Western blotting results showed that cytosolic cytochrome c which was released from mitochondria. Subsequently, tumor suppressor gene p53, pro-apoptotic and anti-apoptotic Bcl-2 family proteins Bax and Bcl-2 were expressed. The caspase cascade reaction was induced through caspase 3 and 9 expression. From these results, it is suggested that myricetin significantly enhanced the apoptosis induced by serum deprivation in a dose-dependent manner in PC12 cells.

Cytotoxic effects of cadmium and zinc co-exposure in PC12 cells and the underlying mechanism.

Cadmium (Cd2+) is a well studied inducer of cellular necrosis and apoptosis. Zinc (Zn2+) is known to inhibit apoptosis induced by toxicants including Cd2+ both in vitro and in vivo. The mechanism of Zn2+-mediated protection from Cd2+-induced cytotoxicity is not established. In this study, we aimed to understand the effects of Zn2+ on Cd2+-induced cytotoxicity and apoptosis using PC12 cells. Cell viability and DNA fragmentation assays in PC12 cells exposed to Cd2+ and/or Zn2+ revealed that Cd2+ (5 and 10 µmol/L) alone induced significant cell death, and co-exposure to Zn2+ (5, 10, and 100 µmol/L) for 48 h had a protective effect. Assessment of intracellular free sulfhydryl levels and lactate dehydrogenase activity suggested that Cd2+ (10 µmol/L) induced oxidative stress and disrupted cell membrane integrity. Addition of Zn2+ (10 and 100 µmol/L) reduced Cd2+-mediated cytotoxicity. Changes in expression of the apoptotic factors Bax, Bcl-2, Bcl-x, and cytochrome c were measured via western blot and expression of caspase 9 was detected via reverse transcriptase polymerase chain reaction. Western blots showed that Zn2+ (10 and 100 µmol/L) suppressed Cd2+-induced apoptosis (10 µmol/L) by reducing cytochrome c release into the cytosol, and downregulating the proapoptotic protein, Bax. In addition, expression of caspase 9 was lower in Cd2+ (5 µmol/L)-treated PC12 cells when co-treated with Zn2+ (2 and 5 µmol/L). These findings suggest that the effective inhibition of Cd2+-induced apoptosis in PC12 cells by Zn2+ might be due to suppression of mitochondrial apoptosis pathway and inhibition of Cd2+-induced production of reactive oxygen species.