Association between adverse childhood experiences and self-reported health-risk behaviors among cancer survivors: A population-based study.

AIMS: Existing evidence shows that people who report Adverse Childhood Experiences (ACEs) are more likely to exhibit health-risk behaviors. However, limited research on this topic pertains to oncology population. We aim to address this knowledge gap by estimating the prevalence of ACEs and investigating their association with self-reported health-risk behaviors among adult cancer survivors living in the U.S. METHODS: We conducted a secondary analysis using cross-sectional data from the 2021 Behavioral Risk Factor Surveillance System ACE module. We included 4,126 adults, aged ≥18 years, with a history of cancer. The outcome variable was self-reported health-risk behaviors, which included cigarette smoking, e-cigarette use, and binge alcohol drinking. Self-reported ACEs history was the primary independent variable, comprised of 11 questions regarding child abuse and dysfunctional households. We conducted descriptive statistics and multivariable logistic regression to describe the relationship between the ACE history and health-risk behaviors. RESULTS: Overall, 84.2% of cancer survivors self-reported as White, 58.4% were women, and 76.6% were aged 65+ years. Nearly two-thirds of the sample (63.2%) self-reported at least one ACE (prior to age 18) and 21.7% engaged in ≥1 health-risk-behaviors, such as cigarette smoking, binge alcohol drinking, or e-cigarette use. Experiencing ≥3 ACEs was associated with 145% increased odds of reporting at least one health-risk behavior (OR = 2.45, 95% CI [1.78-3.38]) when compared to those without a history of ACEs. Besides, survivors who were younger, divorced, less educated, and had low income had higher odds of reporting at least one health-risk behavior. CONCLUSIONS: Overall, a history of ACEs is associated with health-risk behaviors. These all can negatively impact cancer survivors' overall well-being. Early screening for ACE during oncologic visits can be a protective measure for preventing health-risk behaviors among cancer survivors.

Lung cancer screening use among screening-eligible adults with disabilities.

BACKGROUND: Lung cancer screening (LCS) use among adults with disabilities has not been well characterized. We estimated the prevalence of LCS use by disability types and counts and investigated the association between disability counts and LCS utilization among LCS-eligible adults. METHODS: We used cross-sectional data from the 2019 Behavioral Risk Factor Surveillance System, Lung Cancer Screening Module. Based on the 2013 US Preventive Services Task Force criteria for LCS, the sample included 4407 LCS-eligible adults, aged 55-79 years, with current or former (quit smoking in the past 15 years) tobacco use history of at least 30 pack-years. Disability types included limitations in hearing, vision, cognition, mobility, self-care, and independent living. We also categorized respondents by number of disabilities (no disability, 1 disability, 2 disabilities, 3+ disabilities). We utilized descriptive statistics and multivariable logistic regression analyses to determine the association between disability counts and the receipt of LCS (yes/no) in the past 12 months. RESULTS: In 2019, 16.4% of LCS-eligible adults were screened for lung cancer. Overall, 49.6% of participants had no disability, and 14.5% had >3 disabilities. Mobility was the most prevalent disability type (35.4%), followed by cognitive impairment (18.2%) and hearing (16.6%). LCS was more prevalent in adults with disability in self-care versus no disability in self-care (24.0% vs. 15.5%, p = 0.01), disability in independent living versus no disability in independent living (22.2% vs. 15.4%, p = 0.02), and cognitive impairment disability versus no cognitive impairment (22.1% vs. 15.3%, p = 0.03). The prevalence rates of LCS among groups of LCS-eligible adults with different disability counts were not significant (p = 0.17). CONCLUSIONS: Despite the lack of clinical guidelines on LCS among individuals with disabilities, some individuals with disabilities are being screened for lung cancer. Future research should address this knowledge gap to determine clinical benefit versus harm of LCS among those with disabilities.

Prevalence and Correlates of Cannabis Use among U.S. Veterans during the Second Wave of the COVID-19 Pandemic.

INTRODUCTION: Military veterans are at increased risk of substance use disorders. Limited research is available about veterans' cannabis use (CU) during the coronavirus disease 2019 (COVID-19) pandemic. This study estimated the prevalence of past 30-day CU, investigated individual-level correlates of past 30-day CU, and evaluated the reasons (medical, recreational, or both) of past 30-day CU among U.S. Veterans during the second wave of the COVID-19 pandemic. MATERIALS AND METHODS: We used population-based, cross-sectional data from the 2021 Behavioral Risk Factor Surveillance System Survey Marijuana Use model. The sample included nationally representative military veterans aged 18+ years (n = 11,167). The outcome was past 30-day CU. Individual-level demographic, socioeconomic, behavioral, and clinical correlates were examined. Analyses were weighted to account for the survey's complex design with results generalizable to nearly 2.9 million veterans. We conducted weighted descriptive statistics, prevalence estimates, and multivariable logistic regression analyses. RESULTS: Out of 2.9 million veterans, 11.1% self-reported as non-Hispanic Black, 3.7% Hispanic, and 79.1% non-Hispanic White; 88.5% were men, and 72.8% were aged 50+ years. About 14.6% were current tobacco smokers, 4.7% were current e-cigarette users, 12.5% were binge alcohol drinkers, and 43.4% had three or more comorbid conditions. Overall, 8.5% reported CU in the past 30 days, of which 30.4% used it for medical reasons and 25.8% used it for nonmedical reasons. The prevalence of past 30-day CU decreased with age, education, and income level. Compared to their counterparts, the odds of past 30-day CU were greater among men, those living in urban areas, those with frequent mental distress, infrequent physical distress, and those who had at least one comorbid condition. Non-Hispanic Black veterans had 89% increased odds of past 30-day CU (adjusted odds ratio [AOR] =1.89, 95% confidence interval [CI], 1.19-3.0) compared with non-Hispanic White veterans. Current tobacco smokers had 3.54 (95% CI, 2.40-5.24) and former smokers had 1.78 (95% CI, 1.28-2.47) times higher odds of reporting past 30-day CU than never smokers. Current e-cigarette use (AOR = 3.37, 95% CI, 2.20-5.16) and binge drinking (AOR = 3.18, 95% CI, 2.29-4.41) were also statistically significantly associated with increased odds of past 30-day CU compared to no e-cigarette use and no binge drinking. CONCLUSIONS: CU is prevalent among veterans, and certain subgroups are at higher risk of CU. Thus, identifying high-risk subgroups of veterans and adequately educating them about CU's benefits, risks, and safety is crucial.

The role of financial security in loneliness or sadness among Medicare-enrolled cancer survivors during the COVID-19 pandemic.

INTRODUCTION: This study aims to estimate the relative decreased rate of financial security and increased rate of loneliness or sadness during the COVID-19 pandemic and investigate the association between financial security and loneliness or sadness among Medicare beneficiaries with a cancer history. MATERIAL AND METHODS: We examined population-based, cross-sectional data from the Medicare Current Beneficiary Survey COVID-19 Winter 2021 survey. The study cohort included 1,632 Medicare beneficiaries (aged ≥65 years) with self-reported cancer history. The outcome was feelings of loneliness or sadness, and the independent variable was financial security during the 2020-2021 winter surge of COVID-19. We conducted weighted descriptive statistics, a cross-tabulation analysis, and multivariable logistic regression analyses. RESULTS: Overall, 18.8% of cancer survivors reported increased feelings of loneliness or sadness and 11.2% reported decreased financial security during the 2020-2021 winter surge of COVID-19. Cancer survivors who reported decreased financial security had 93% higher odds of increased feelings of loneliness or sadness compared to those who reported feeling more or about the same financial security (Adjusted odds ratio [AOR] = 1.93; 95% Confidence Interval [CI] 1.25-3.01; p <0.004). DISCUSSION: Decreased financial security and increased feelings of loneliness or sadness were prevalent among cancer survivors. Additional screenings and interventions beyond what are currently available are needed to ease the socioeconomic vulnerabilities experienced by cancer survivors.

Cannabis use among cancer survivors before and during the COVID-19 pandemic, 2019-2021.

We estimated the prevalence of past 30-day cannabis use, evaluated reasons for use, and identified individual-level factors associated with cannabis use among cancer survivors before (2019) and during (2020 and 2021) the COVID-19 pandemic. Cancer survivors, aged 18 years and older, were identified from the 2019 (n = 8185), 2020 (n = 11 084), and 2021 (n = 12 248) Behavioral Risk Factor Surveillance System. Prevalence of past 30-day cannabis use among survivors held steady through the pandemic (8.7%, 7.4%, and 8.4% in 2019, 2020 and 2021, respectively). Of those who used cannabis, 48.7% used it for medical reasons in 2019, 54.5% in 2020, and 43.5% in 2021. Survivors were more likely to report past 30-day cannabis use if they were younger, male, current or former tobacco smokers, and binge alcohol consumers and if they experienced poor mental health in the past 30-days. Our study identified subpopulations of cancer survivors that need to be targeted for evidence-informed discussions about cannabis use.

Novel nicotinamide analog as inhibitor of nicotinamide N-methyltransferase.

Nicotinamide N-methyltransferase (NNMT) has been linked to obesity and diabetes. We have identified a novel nicotinamide (NA) analog, compound 12 that inhibited NNMT enzymatic activity and reduced the formation of 1-methyl-nicotinamide (MNA), the primary metabolite of NA by ∼80% at 2 h when dosed in mice orally at 50 mg/kg.

A Glycomic Approach Towards Identification of Signature Molecules in CD34+ Haematopoietic Stem Cells from Umbilical Cord Blood.

Umbilical cord blood (UCB) is a powerful storehouse for normal CD34+ haematopoietic stem cells (HSCs), often used for allogeneic bone marrow (BM) transplantation in malignant and non-malignant diseases. The glycomic especially the sialoglycomic aspect of these HSCs has been unravelled in this study. Cell surface expression of the glycans with the related enzymatic activities has been compared with the BM of childhood acute lymphoblastic leukaemia, a common BM-associated malignancy. An enhanced cell surface expression of α2,3-linked sialic acid, P- and E-selectins, and intercellular adhesion molecule along with reduced expression of L-selectin distinguishes CD34+ HSCs of UCB from leukaemic samples. More importantly, high expression of O-acetylated sialoglycoproteins, a hallmark of lymphoblasts, is drastically reduced in the CD34+ HSCs of UCB and is substantiated by the low activity of sialylate-O-acetyltransferase and high sialidase activity. In contrast, a significant variation is evident in the expression of sialic acid, α2,6-linked sialic acids, and the sialyltransferase activity. Taken together, these studies indicate a few signature molecules, forming a unique glycomic template, which may be a potential indicator, reassuring the normal profile of these stem cells, to be used for future transplantation.

Disialoganglioside GD3-synthase over expression inhibits survival and angiogenesis of pancreatic cancer cells through cell cycle arrest at S-phase and disruption of integrin-ß1-mediated anchorage.

Gangliosides play important roles in the development, differentiation and proliferation of mammalian cells. They bind to other cell membrane components through their terminal sialic acids. Different gangliosides influence cellular functions based on the positions and linkages of sialic acids. Expression of gangliosides mainly depends on the status of sialic acid-modulatory enzymes, such as different types of sialyltransferases and sialidases. One such sialyltransferase, disialoganglioside GD3 synthase, is specifically responsible for the production of GD3. Pancreatic ductal adenocarcinoma, making up more than 90% of pancreatic cancers, is a fatal malignancy with poor prognosis. Despite higher sialylation status, the disialoganglioside GD3 level is very low in this cancer. However, the exact status and function of this disialoganglioside is still unknown. Here, we intended to study the intracellular mechanism of disialoganglioside GD3-induced apoptosis and its correlation with the adhesion and angiogenic pathways in pancreatic cancer. We demonstrated that disialoganglioside GD3 synthase-transfected cells showed enhanced apoptosis and it caused the arrest of these cells in the S-phase of the cell cycle. Integrins, a family of transmembrane proteins play important role in cell-cell recognition, invasion, adhesion and migration. disialoganglioside GD3 co-localised with integrin-ß1 and thereby inhibited it's downstream signalling in transfected cells. Transfected cells exhibited inhibition of cell adhesion with extracellular matrix proteins. Enhanced GD3 expression down regulated angiogenesis-regulatory proteins and inhibited epidermal growth factor/vascular endothelial growth factor-driven angiogenic cell growth in these cells. Taken together, our study provides support for the GD3-induced cell cycle arrest, disruption of integrin-ß1-mediated anchorage, inhibition of angiogenesis and thereby induced apoptosis in pancreatic cancer cells.

Coupling G2/M arrest to the Wnt/ß-catenin pathway restrains pancreatic adenocarcinoma.

ß-catenin plays a pivotal role in organogenesis and oncogenesis. Alterations in ß-catenin expression are common in pancreatic cancer, which is an extremely aggressive malignancy with a notably poor prognosis. In this report, we analyzed the apoptotic activity of withanolide-D (witha-D), a steroidal lactone that was purified from an Indian medicinal plant, Withania somnifera, and its underlying mechanism of action. Witha-D induced apoptosis in pancreatic ductal adenocarcinoma cells by prompting cell-cycle arrest at the G2/M phase. This lactone abrogated ß-catenin signaling in these cells regardless of disease grade, mutational status, and gemcitabine sensitivity. Witha-D also upregulated E-cadherin in most cells, thereby supporting the inversion of the epithelial-mesenchymal transition. Furthermore, the Akt/Gsk3ß kinase cascade was identified as a critical mediator of G2/M regulation and ß-catenin signaling. Witha-D deactivated Akt, which failed to promote Gsk3ß deactivation phosphorylation. Consequently, activated Gsk3ß facilitated ß-catenin destruction in pancreatic carcinoma cells. The knockdown of Chk1 and Chk2 further activated Akt and reversed the molecular signal. Taken together, the results of the current study represent the first evidence of ß-catenin signal crosstalk during the G2/M phase by functionally inactivating Akt via witha-D treatment in pancreatic cancer cells. In conclusion, this finding suggests the potential identification of a new lead molecule in the treatment of pancreatic adenocarcinoma.

Mahanine synergistically enhances cytotoxicity of 5-fluorouracil through ROS-mediated activation of PTEN and p53/p73 in colon carcinoma.

5-Fluorouracil (5-FU) alone or in combination with other drugs is the main basis of chemotherapeutic treatment in colorectal cancer although patients with microsatellite instability generally show resistance to 5-FU treatment. The present investigation is focussed on the mechanistic insight of a pure herbal carbazole alkaloid, mahanine, as a single or in combination with 5-FU in colon cancer. We demonstrated that mahanine-induced apoptosis involved reactive oxygen species (ROS)-mediated nuclear accumulation of PTEN and its interaction with p53/p73. Mahanine and 5-FU in combination exerted synergistic inhibitory effect on cell viability. This combination also enhanced ROS production, increased tumour suppressor proteins and suppressed chemo-migration. Taken together, our results revealed that mahanine can be a potential chemotherapeutic agent with efficacy to reduce the concentration of toxic 5-FU in colon cancer.

Mahanine, a DNA minor groove binding agent exerts cellular cytotoxicity with involvement of C-7-OH and -NH functional groups.

Mahanine, a carbazole alkaloid is a potent anticancer molecule. To recognize the structure-activity correlation, mahanine was chemically modified. Antiproliferative activity of these derivatives was determined in 19 cancer cell lines from 7 different origins. Mahanine showed enhanced apoptosis compared to dehydroxy-mahanine-treated cells, indicating significant contribution of the C-7-OH group. O-Methylated-mahanine and N-methylated dehydroxy-mahanine-treated cells exhibited apoptosis only at higher concentrations, suggesting additional contribution of 9-NH group. Using biophysical techniques, we demonstrated that mahanine interacts with DNA through strong association with phosphate backbone compared to other derivatives but is unable to induce any conformational change in DNA, hence suggesting the possibility of being a minor groove binder. This was corroborated by molecular modeling and isothermal titration calorimetry studies. Taken together, the results of the current study represent the first evidence of involvement of C-7-OH and 9-NH group of mahanine for its cytotoxicity and its minor groove binding ability with DNA.

Oxidative inhibition of Hsp90 disrupts the super-chaperone complex and attenuates pancreatic adenocarcinoma in vitro and in vivo.

Pancreatic cancer is almost always fatal, in part because of its delayed diagnosis, poor prognosis, rapid progression and chemoresistance. Oncogenic proteins are stabilized by the Hsp90, making it a potential therapeutic target. We investigated the oxidative stress-mediated dysfunction of Hsp90 and the hindrance of its chaperonic activity by a carbazole alkaloid, mahanine, as a strategic therapeutic in pancreatic cancer. Mahanine exhibited antiproliferative activity against several pancreatic cancer cell lines through apoptosis. It induced early accumulation of reactive oxygen species (ROS) leading to thiol oxidation, aggregation and dysfunction of Hsp90 in MIAPaCa-2. N-acetyl-L-cysteine prevented mahanine-induced ROS accumulation, aggregation of Hsp90, degradation of client proteins and cell death. Mahanine disrupted Hsp90-Cdc37 complex in MIAPaCa-2 as a consequence of ROS generation. Client proteins were restored by MG132, suggesting a possible role of ubiquitinylated protein degradation pathway. Surface plasmon resonance study demonstrated that the rate of interaction of mahanine with recombinant Hsp90 is in the range of seconds. Molecular dynamics simulation showed its weak interactions with Hsp90. However, no disruption of the Hsp90-Cdc37 complex was observed at an early time point, thus ruling out that mahanine directly disrupts the complex. It did not impede the ATP binding pocket of Hsp90. Mahanine also reduced in vitro migration and tube formation in cancer cells. Further, it inhibited orthotopic pancreatic tumor growth in nude mice. Taken together, these results provide evidence for mahanine-induced ROS-mediated destabilization of Hsp90 chaperone activity resulting in Hsp90-Cdc37 disruption leading to apoptosis, suggesting its potential as a specific target in pancreatic cancer.

Mobilization of lymphoblasts from bone marrow to peripheral blood in childhood acute lymphoblastic leukaemia: role of 9-O-acetylated sialoglycoproteins.

Childhood acute lymphoblastic leukaemia is characterized by aberrant proliferation and accumulation of malignant lymphoblasts in bone marrow (BM), followed by their migration into circulation. An enhanced cell-surface expression of ALL-associated 9-O-acetylated sialoglycoproteins (Neu5,9Ac(2)-GPs) was demonstrated. Present investigation reports a positive correlation between the increased density of Neu5,9Ac(2)-GPs on lymphoblasts and their mobilization from BM involving enhanced Neu5,9Ac(2) on CD45 demonstrating modulation of FAK and ERK molecules. In contrast, a small population of cells, identified as haematopoietic precursors, with comparatively lesser Neu5,9Ac(2)-GPs showed increased binding towards BM stroma. Thus, Neu5,9Ac(2)-GPs is a developmentally regulated oncofoetal antigen, whose up-regulation is imperative in the interaction between lymphoblasts and BM stroma, governing their mobilization into circulation.