Size and position matter.

The 2013 Nobel Prize in Physiology or Medicine emphasizes the progress made in understanding the molecular mechanisms that underpin the vesicular movement of cargo through the exocytic and endocytic pathways. Attention now focuses on those mechanisms that govern the relative size and position of the many different membrane-bound compartments. These homeostatic mechanisms are discussed in this issue of Nature Reviews Molecular Cell Biology and must be integrated so as to satisfy the needs of the cell and the organism.

Implementation, enrollment, and engagement in an opt-out telehealth pharmacist-assisted tobacco treatment program for patients seen in oncology outpatient clinics.

OBJECTIVE: To describe the workflow, reach, cost, and self-reported quit rates for an opt-out tobacco treatment program (TTP) for patients seen in 43 oncology outpatient clinics. METHODS: Between May 25, 2021, and December 31, 2022, adult patients (≥18 years) visiting clinics affiliated with the Medical University of South Carolina Hollings Cancer Center were screened for smoking status. Those currently smoking were referred to a telehealth pharmacy-assisted TTP. An attempt was made to contact referred patients by phone. Patients reached were offered free smoking cessation counseling and a 2-week starter kit of nicotine replacement medication. A random sample of 420 patients enrolled in the TTP were selected to participate in a telephone survey to assess smoking status 4 to 12 months after enrollment. RESULTS: During the reference period 35,756 patients were screened and 9.3% were identified as currently smoking. Among the 3319 patients referred to the TTP at least once, 2393 (72.1%) were reached by phone, of whom 426 (12.8%) were ineligible for treatment, 458 (13.8%) opted out of treatment, and 1509 (45.5%) received treatment. More than 90% of TTP enrollees smoked daily, with an average of 13.1 cigarettes per day. Follow-up surveys were completed on 167 of 420 patients, of whom 23.4% to 33.5% reported not smoking; if all nonresponders to the survey are counted as smoking, the range of quit rates is 9.3% to 13.3%. CONCLUSION: The findings demonstrate the feasibility of reaching and delivering smoking cessation treatments to patients from a diverse set of geographically dispersed oncology clinics.

The Impact of the COVID-19 Pandemic on Tobacco Treatment Program Implementation at National Cancer Institute-Designated Cancer Centers.

INTRODUCTION: The COVID-19 pandemic disrupted cancer screening and treatment delivery, but COVID-19's impact on tobacco cessation treatment for cancer patients who smoke has not been widely explored. AIMS AND METHODS: We conducted a sequential cross-sectional analysis of data collected from 34 National Cancer Institute (NCI)-designated cancer centers participating in NCI's Cancer Center Cessation Initiative (C3I), across three reporting periods: one prior to COVID-19 (January-June 2019) and two during the pandemic (January-June 2020, January-June 2021). Using McNemar's Test of Homogeneity, we assessed changes in services offered and implementation activities over time. RESULTS: The proportion of centers offering remote treatment services increased each year for Quitline referrals (56%, 68%, and 91%; p = .000), telephone counseling (59%, 79%, and 94%; p = .002), and referrals to Smokefree TXT (27%, 47%, and 56%; p = .006). Centers offering video-based counseling increased from 2020 to 2021 (18% to 59%; p = .006), Fewer than 10% of centers reported laying off tobacco treatment staff. Compared to early 2020, in 2021 C3I centers reported improvements in their ability to maintain staff and clinician morale, refer to external treatment services, train providers to deliver tobacco treatment, and modify clinical workflows. CONCLUSIONS: The COVID-19 pandemic necessitated a rapid transition to new telehealth program delivery of tobacco treatment for patients with cancer. C3I cancer centers adjusted rapidly to challenges presented by the pandemic, with improvements reported in staff morale and ability to train providers, refer patients to tobacco treatment, and modify clinical workflows. These factors enabled C3I centers to sustain evidence-based tobacco treatment implementation during and beyond the COVID-19 pandemic. IMPLICATIONS: This work describes how NCI-designated cancer centers participating in the Cancer Center Cessation Initiative (C3I) adapted to challenges to sustain evidence-based tobacco use treatment programs during the COVID-19 pandemic. This work offers a model for resilience and rapid transition to remote tobacco treatment services delivery and proposes a policy and research agenda for telehealth services as an approach to sustaining evidence-based tobacco treatment programs.

Smoking Status, Nicotine Medication, Vaccination, and COVID-19 Hospital Outcomes: Findings from the COVID EHR Cohort at the University of Wisconsin (CEC-UW) Study.

INTRODUCTION: Available evidence is mixed concerning associations between smoking status and COVID-19 clinical outcomes. Effects of nicotine replacement therapy (NRT) and vaccination status on COVID-19 outcomes in smokers are unknown. METHODS: Electronic health record data from 104 590 COVID-19 patients hospitalized February 1, 2020 to September 30, 2021 in 21 U.S. health systems were analyzed to assess associations of smoking status, in-hospital NRT prescription, and vaccination status with in-hospital death and ICU admission. RESULTS: Current (n = 7764) and never smokers (n = 57 454) did not differ on outcomes after adjustment for age, sex, race, ethnicity, insurance, body mass index, and comorbidities. Former (vs never) smokers (n = 33 101) had higher adjusted odds of death (aOR, 1.11; 95% CI, 1.06-1.17) and ICU admission (aOR, 1.07; 95% CI, 1.04-1.11). Among current smokers, NRT prescription was associated with reduced mortality (aOR, 0.64; 95% CI, 0.50-0.82). Vaccination effects were significantly moderated by smoking status; vaccination was more strongly associated with reduced mortality among current (aOR, 0.29; 95% CI, 0.16-0.66) and former smokers (aOR, 0.47; 95% CI, 0.39-0.57) than for never smokers (aOR, 0.67; 95% CI, 0.57, 0.79). Vaccination was associated with reduced ICU admission more strongly among former (aOR, 0.74; 95% CI, 0.66-0.83) than never smokers (aOR, 0.87; 95% CI, 0.79-0.97). CONCLUSIONS: Former but not current smokers hospitalized with COVID-19 are at higher risk for severe outcomes. SARS-CoV-2 vaccination is associated with better hospital outcomes in COVID-19 patients, especially current and former smokers. NRT during COVID-19 hospitalization may reduce mortality for current smokers. IMPLICATIONS: Prior findings regarding associations between smoking and severe COVID-19 disease outcomes have been inconsistent. This large cohort study suggests potential beneficial effects of nicotine replacement therapy on COVID-19 outcomes in current smokers and outsized benefits of SARS-CoV-2 vaccination in current and former smokers. Such findings may influence clinical practice and prevention efforts and motivate additional research that explores mechanisms for these effects.

Negative affect and the utilization of tobacco treatment among adult smokers with cancer.

OBJECTIVE: We investigated the patterns of tobacco treatment utilization among US adult smokers with cancer and the role of negative affect as potential individual-level psychosocial barriers and facilitators influencing quit attempts and tobacco treatment utilization. METHODS: We analyzed data from the adult sample in Wave 1 (2013-2014) of the Population Assessment of Tobacco and Health (PATH) Study. Using structural equation modeling, we examined (1) the association between cancer diagnosis and negative affect (e.g., depressive mood, anxiety, and distress) and (2) the associations between negative affect and smoking cessation behaviors (i.e., quit attempts and tobacco treatment utilization). RESULTS: Compared to adults without cancer, cancer survivors were more likely to have attempted to quit tobacco use in the past 12 months (p < 0.05) and experienced increased negative affect (p < 0.01). However, negative affect appeared to be a psychological barrier to quit attempts, as it was associated with lower likelihood of attempting to quit (p < 0.05). On the other hand, among past-12-month quit attempters, negative affect was related to higher likelihood of using any type of tobacco treatment (p < 0.001). CONCLUSIONS: Negative affect may be a potential underlying mechanism in the relationship between cancer diagnosis status and quit attempts and tobacco treatment utilization, influencing the utilization of tobacco treatment among smokers with cancer. Research is needed to investigate whether integrating emotional management in the oncology setting may effectively aid smoking cessation among patients with cancer.

Cost evaluation of tobacco control interventions in clinical settings: A systematic review.

Elucidating the cost implications of tobacco control interventions is a prerequisite to their adoption in clinical settings. This review fills a knowledge gap in characterizing the extent to which cost is measured in tobacco control studies. A search of English literature was conducted in the following electronic databases: MEDLINE, EconLit, PsychINFO, and CINAHL using MeSH terms from 2009 to 2018. Studies were reviewed by two independent reviewers and included if they were conducted in U.S. inpatient or outpatient facilities and reported costs associated with a tobacco control intervention. They were categorized according to evaluation type, clinical setting, target population, cost measures, and stakeholder perspective. Bias risk was evaluated for RCTs. Seventeen publications were included, representing counseling interventions (n = 8) and combination (i.e., counseling and pharmacotherapy) interventions (n = 9). Studies were categorized by evaluation type: cost-effectiveness analysis (n = 10), cost utility analysis (n = 3) and cost identification (n = 4). The selected studies targeted the following populations: general adults (n = 6), hospitalized/inpatient (n = 4), military/veterans (n = 4), individuals with low socioeconomic status (n = 4), mental health or medical comorbidities (n = 2), and pregnant women (n = 2). Intervention costs included personnel, medication, education material, technology, and overhead costs. Stakeholder perspectives included: healthcare organization (n = 10), payer (n = 8), patient (n = 2), and societal (n = 1). Few studies have reported the cost of tobacco control interventions in clinical settings. Cost is a critical outcome that should be consistently measured in evaluations of tobacco control interventions to promote their uptake in clinical settings.

Modeling rectal cancer to advance neoadjuvant precision therapy.

Progress in rectal cancer therapy has been hindered by the lack of effective disease-specific preclinical models that account for the unique molecular profile and biology of rectal cancer. Thus, we developed complementary patient-derived xenograft (PDX) and subsequent in vitro tumor organoid (PDTO) platforms established from preneoadjuvant therapy rectal cancer specimens to advance personalized care for rectal cancer patients. Multiple endoscopic samples were obtained from 26 Stages 2 and 3 rectal cancer patients prior to receiving 5FU/RT and implanted subcutaneously into NSG mice to generate 15 subcutaneous PDXs. Second passaged xenografts demonstrated 100% correlation with the corresponding human cancer histology with maintained mutational profiles. Individual rectal cancer PDXs reproduced the 5FU/RT response observed in the corresponding human cancers. Similarly, rectal cancer PDTOs reproduced significant heterogeneity in cellular morphology and architecture. PDTO in vitro 5FU/RT treatment response replicated the clinical 5FU/RT neoadjuvant therapy pathologic response observed in the corresponding patient tumors (p < 0.05). The addition of cetuximab to the 5FU/RT regiment was significantly more sensitive in the rectal cancer PDX and PDTOs with wild-type KRAS compared to mutated KRAS (p < 0.05). Considering the close relationship between the patient's cancer and the corresponding PDX/PDTO, rectal cancer patient-derived research platforms represent powerful translational research resources as population-based tools for biomarker discovery and experimental therapy testing. In addition, our findings suggest that cetuximab may enhance RT effectiveness by improved patient selection based on mutational profile in addition to KRAS or by developing a protocol using PDTOs to identify sensitive patients.

Considering Systemic Barriers to Treating Tobacco Use in Clinical Settings in the United States.

The Comorbidity Workgroup of the Tobacco Treatment Research Network, within the Society for Research on Nicotine and Tobacco, previously highlighted the need to provide tobacco treatment to patients diagnosed with comorbid physical and mental health conditions. Yet, systemic barriers in the United States health care system prevent many patients who present for medical treatment from getting the evidence-based tobacco treatment that they need. The identified barriers include insufficient training in the epidemiologic impact of tobacco use, related disorders, and pharmacological and behavioral treatment approaches; misunderstanding among clinicians about the effectiveness of tobacco treatment; lack of therapeutic support from clinical staff; insufficient use of health information technology to improve tobacco use identification and treatment; and limited time and reimbursement for clinicians to provide treatment. We highlight three vignettes demonstrating the complexities of practical barriers at the health care system level. We consider each of the barriers in turn and discuss evidence-based strategies that could be implemented in the clinical care of patients with comorbid conditions. In addition, in the absence of compelling data to guide implementation approaches, we offer suggestions for potential strategies and avenues for future research. Implications: Three vignettes highlighted in this article illustrate some systemic barriers to providing tobacco treatment for patients being treated for comorbid conditions. We explore the barriers to tobacco treatment and offer suggestions for changes in training, health care systems, clinical workflow, and payment systems that could enhance the reach and the quality of tobacco treatment within the US health care system.

SIRT2 regulates nuclear envelope reassembly through ANKLE2 deacetylation.

Sirtuin 2 (SIRT2) is an NAD-dependent deacetylase known to regulate microtubule dynamics and cell cycle progression. SIRT2 has also been implicated in the pathology of cancer, neurodegenerative diseases and progeria. Here, we show that SIRT2 depletion or overexpression causes nuclear envelope reassembly defects. We link this phenotype to the recently identified regulator of nuclear envelope reassembly ANKLE2. ANKLE2 acetylation at K302 and phosphorylation at S662 are dynamically regulated throughout the cell cycle by SIRT2 and are essential for normal nuclear envelope reassembly. The function of SIRT2 therefore extends beyond the regulation of microtubules to include the regulation of nuclear envelope dynamics.

Effect of an Evidence-based Inpatient Tobacco Dependence Treatment Service on 1-Year Postdischarge Health Care Costs.

BACKGROUND: In 2014, the Medical University of South Carolina (MUSC) implemented a Tobacco Dependence Treatment Service (TDTS) consistent with the Joint Commission (JC) standards recommending that hospitals screen patients for smoking, provide cessation support, and follow-up contact for relapse prevention within 1 month of discharge. We previously demonstrated that patients exposed to the MUSC TDTS were approximately half as likely to be smoking one month after discharge and 23% less likely to have a 30-day hospital readmission. This paper examines whether exposure to the TDTS influenced downstream health care charges 12 months after patients were discharged from the hospital. METHODS: Data from MUSC's electronic health records, the TDTS, and statewide health care utilization datasets (eg, hospitalization, emergency department, and ambulatory surgery visits) were linked to assess how exposure to the MUSC TDTS impacted health care charges. Total health care charges were compared for patients with and without TDTS exposure. To reduce potential TDTS exposure selection bias, propensity score weighting was used to balance baseline characteristics between groups. The cost of delivering the MUSC TDTS intervention was calculated, along with cost per smoker. RESULTS: The overall adjusted mean health care charges for smokers exposed to the TDTS were $7299 lower than for those who did not receive TDTS services (P=0.047). The TDTS cost per smoker was modest by comparison at $34.21 per smoker eligible for the service. DISCUSSION: Results suggest that implementation of a TDTS consistent with JC standards for smoking cessation can be affordably implemented and yield substantial health care savings that would benefit patients, hospitals, and insurers.

Effect of an Evidence-based Inpatient Tobacco Dependence Treatment Service on 30-, 90-, and 180-Day Hospital Readmission Rates.

INTRODUCTION: Smoking is a risk factor for hospitalization and interferes with patient care due to its effects on pulmonary function, wound healing, and interference with treatments and medications. Although benefits of stopping smoking are well-established, few hospitals provide tobacco dependence treatment services (TDTS) due to cost, lack of mandatory tobacco cessation standards and lack of evidence demonstrating clinical and financial benefits to hospitals and insurers for providing services. METHODS: This study explored the effect of an inpatient TDTS on 30-, 90-, and 180-day hospital readmissions. To carry out this work, 3 secondary datasets were linked, which included clinical electronic health record data, tobacco cessation program data, and statewide health care utilization data. Odds ratios (ORs) were calculated using inverse propensity score-weighted logistic regression models, with program exposure as the primary independent variable and 30 (90 and 180)-day readmission rates as the dependent variable, and adjustment for putative covariates. RESULTS: Odds of readmission were compared for patients who did and did not receive TDTS. At 30 days postdischarge, smokers exposed to the TDTS had a lower odds of readmission (OR=0.77, P=0.031). At 90 and 180 days, odds of readmission remained lower in the TDTS group (ORs=0.87 and 0.86, respectively), but were not statistically significant. DISCUSSION: Findings from the current study, which are supported by prior studies, provide evidence that delivery of TDTS is a strategy that may help to reduce hospital readmissions.

Evaluation of a Dedicated Tobacco Cessation Support Service for Thoracic Cancer Center Patients.

CONTEXT: Cancer patients' continued tobacco use results in poorer therapeutic outcomes including decreased quality of life and survival. OBJECTIVE: To assess reach and impact of a free, opt-out, telephone-based tobacco cessation program for thoracic cancer center patients. DESIGN: Observational study. SETTING: Comprehensive Cancer Center in Western New York. PARTICIPANTS: Current or recent (within past 30 days) tobacco-using thoracic cancer center patients referred to a tobacco cessation support service between October 2010 and October 2012 at a Comprehensive Cancer Center (n = 942/1313 referrals were eligible for cessation support). INTERVENTION: A free, opt-out, telephone-based cessation service that was implemented as standard of care. Cessation specialists had patient-guided conversations that assessed readiness to quit; methods used in the past provided cessation strategies and worked to set up a quit date. There was an average of 35.9 days between referral and first contact. MAIN OUTCOME MEASURES: Program reach (referral and participation rates) and impact (as self-reported cessation outcomes measured twice after referral). RESULTS: Of 942 patients, 730 (77.5%) referred to and called by a tobacco cessation service participated in at least 1 cessation support call, of which 440 of 730 (60.3%) were called for follow-up and 89.5% (394/440) participated. In total, 20.2% (69/342) of current smokers at referral reported at least 7-day abstinence at follow-up. Among current smokers at referral and first contact, being married (odds ratio [OR] = 2.05; 95% confidence interval [CI], 1.01-4.18) and having a lower Eastern Cooperative Oncology Group (ECOG) performance score (OR = 4.05; 95% CI, 1.58-10.39) were associated with quitting at follow-up, after controlling for demographic, clinical, and health behavior characteristics. CONCLUSIONS: Our results demonstrate that 78% of thoracic cancer center patients, if contacted, participated at least once in this cessation support service; for current smokers at referral and first contact, being married and having a lower ECOG performance score were associated with self-reported quitting at follow-up. Other organizations may find our results useful while implementing a systematic way to identify tobacco-using patients as part of routine care and to improve available cessation support services.

Feasibility of Implementing a Hospital-Based "Opt-Out" Tobacco-Cessation Service.

OBJECTIVE: To assess the feasibility and outcomes of implementing a hospital-based "opt-out" tobacco-cessation service. METHODS: In 2014, the Medical University of South Carolina adopted a policy that all hospitalized patients who self-report using tobacco be referred to tobacco-cessation service. This is a descriptive study of a real-world effort to implement guidelines for a hospital-based cessation service consistent with Joint Commission's standards. Between February 2014 and May 2015, 42 061 adults were admitted to the Medical University of South Carolina Hospital. Eligible current cigarette smokers were referred to the tobacco-cessation service, which consisted of a bedside consult and phone follow-up 3, 14, and 30 days after hospital discharge using interactive-voice-response. The primary study outcomes evaluated the proportions of smokers reached by the bedside counselor and/or phone follow-up, smokers who opted out, and smokers who self-reported not smoking when last contacted by phone. RESULTS: Records identified 8423 smokers, of whom 69.4% (n = 5843) were referred into the service. One full-time bedside counselor was able to speak with 1918 (32.8%) patients, of whom 96 (5%) denied currently smoking and 287 (14.9%) refused counselling. Reach at follow-up was achieved for 703 (55%) smokers who received bedside counselling and 1613 (49%) who did not, yielding an overall follow-up reach rate of 60%. Of those reached by phone, 36.4% reported not smoking (51% vs. 27% for those who did and did not receive bedside counselling, respectively). Intent-to-treat abstinence rate was 13.5% according to the last known smoking status. CONCLUSIONS: Findings from this study suggest that an inpatient smoking-cessation service with an "opt-out" approach can positively impact short-term cessation outcomes. IMPLICATIONS: (1) The findings demonstrate the feasibility of implementing an automated large-scale opt-out tobacco-cessation service for hospitalized patients that is consistent with the Joint Commission recommended standards for treating tobacco dependence. (2) Receiving a bedside tobacco-cessation consult while hospitalized increased the use of stop smoking medications and abstinence from smoking after discharge from the hospital. (3) Even in those patients who did not receive a bedside consult, 5% accepted a referral to the South Carolina Tobacco Quitline to get help to stop smoking.

The Association between Smoking Abstinence and Mortality in the National Lung Screening Trial.

RATIONALE: Smoking is the largest contributor to lung cancer risk, and those who continue to smoke after diagnosis have a worse survival. Screening for lung cancer with low-dose computed tomography (LDCT) reduces mortality in high-risk individuals. Smoking cessation is an essential component of a high-quality screening program. OBJECTIVES: To quantify the effects of smoking history and abstinence on mortality in high-risk individuals who participated in the NLST (National Lung Screening Trial). METHODS: This is a secondary analysis of a randomized controlled trial (NLST). MEASUREMENTS AND MAIN RESULTS: Measurements included self-reported demographics, medical and smoking history, and lung cancer-specific and all-cause mortality. Cox regression was used to study the association of mortality with smoking status and pack-years. Kaplan-Meier survival curves were examined for differences in survival based on trial arm and smoking status. Current smokers had an increased lung cancer-specific (hazard ratio [HR], 2.14-2.29) and all-cause mortality (HR, 1.79-1.85) compared with former smokers irrespective of screening arm. Former smokers in the control arm abstinent for 7 years had a 20% mortality reduction comparable with the benefit reported with LDCT screening in the NLST. The maximum benefit was seen with the combination of smoking abstinence at 15 years and LDCT screening, which resulted in a 38% reduction in lung cancer-specific mortality (HR, 0.62; 95% confidence interval, 0.51-0.76). CONCLUSIONS: Seven years of smoking abstinence reduced lung cancer-specific mortality at a magnitude comparable with LDCT screening. This reduction was greater when abstinence was combined with screening, highlighting the importance of smoking cessation efforts in screening programs.

Significance of pregnancy test false negative results due to elevated levels of ß-core fragment hCG.

Very high levels of ß-core fragment human chorionic gonadotrophin (ßcf-hCG) are reported to potentially cause false negative results in point-of-care (POC)/over-the-counter (OTC) pregnancy tests. To investigate this further, women's daily early morning urine samples, collected prior to conception and during pregnancy, were analysed for intact, free ß-, and ßcf-hCG. The proportion of ßcf-hCG was found to be related to that of hCG produced and in circulation. Therefore, best practice for accuracy testing of POC/OTC pregnancy tests would be to test devices against clinical samples containing high levels of ßcf-hCG as well as standards spiked with biologically relevant ratios.

Sec16 determines the size and functioning of the Golgi in the protist parasite, Trypanosoma brucei.

The Sec16 homologue in Trypanosoma brucei has been identified and characterized. TbSec16 colocalizes with COPII components at the single endoplasmic reticulum exit site (ERES), which is next to the single Golgi stack in the insect (procyclic) form of this organism. Depletion of TbSec16 reduces the size of the ERES and the Golgi, and slows growth and transport of a secretory marker to the cell surface; conversely, overexpression of TbSec16 increases the size of the ERES and Golgi but has no effect on growth or secretion. Together these data suggest that TbSec16 regulates the size of the ERES and Golgi and this size is set for optimal growth of the organism.

Cognitive testing of tobacco use items for administration to patients with cancer and cancer survivors in clinical research.

BACKGROUND: To the authors' knowledge, there are currently no standardized measures of tobacco use and secondhand smoke exposure in patients diagnosed with cancer, and this gap hinders the conduct of studies examining the impact of tobacco on cancer treatment outcomes. The objective of the current study was to evaluate and refine questionnaire items proposed by an expert task force to assess tobacco use. METHODS: Trained interviewers conducted cognitive testing with cancer patients aged ≥21 years with a history of tobacco use and a cancer diagnosis of any stage and organ site who were recruited at the National Institutes of Health Clinical Center in Bethesda, Maryland. Iterative rounds of testing and item modification were conducted to identify and resolve cognitive issues (comprehension, memory retrieval, decision/judgment, and response mapping) and instrument navigation issues until no items warranted further significant modification. RESULTS: Thirty participants (6 current cigarette smokers, 1 current cigar smoker, and 23 former cigarette smokers) were enrolled from September 2014 to February 2015. The majority of items functioned well. However, qualitative testing identified wording ambiguities related to cancer diagnosis and treatment trajectory, such as "treatment" and "surgery"; difficulties with lifetime recall; errors in estimating quantities; and difficulties with instrument navigation. Revisions to item wording, format, order, response options, and instructions resulted in a questionnaire that demonstrated navigational ease as well as good question comprehension and response accuracy. CONCLUSIONS: The Cancer Patient Tobacco Use Questionnaire (C-TUQ) can be used as a standardized item set to accelerate the investigation of tobacco use in the cancer setting. Cancer 2016;122:1728-34. © 2016 American Cancer Society.

The endocytic activity of the flagellar pocket in Trypanosoma brucei is regulated by an adjacent phosphatidylinositol phosphate kinase.

Phosphoinositides are spatially restricted membrane signaling molecules. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]--a phosphoinositide that is highly enriched in, and present throughout, the plasma membrane--has been implicated in endocytosis. Trypanosoma brucei has one of the highest known rates of endocytosis, a process it uses to evade the immune system. To determine whether phosphoinositides play a role in endocytosis in this organism, we have identified and characterized one of the enzymes that is responsible for generating PI(4,5)P2. Surprisingly, this phosphoinositide was found to be highly concentrated in the flagellar pocket, the only site of endocytosis and exocytosis in this organism. The enzyme (designated TbPIPKA, annotated as Tb927.10.1620) was present at the neck of the pocket, towards the anterior-end of the parasite. Depletion of TbPIPKA led to depletion of PI(4,5)P2 and enlargement of the pocket, the result of impaired endocytosis. Taken together, these data suggest that TbPIPKA and its product PI(4,5)P2 are important for endocytosis and, consequently, for homeostasis of the flagellar pocket.

Smoking may modify the association between neoadjuvant chemotherapy and survival from ovarian cancer.

OBJECTIVE: Tobacco smoking by cancer patients is associated with increased mortality. Less is known of the impact of smoking on recurrence risk and interaction with chemotherapy treatment. We examined these associations in ovarian cancer. METHODS: Patients were identified from the Alberta Cancer Registry between 1978 and 2010 and were oversampled for less-common histologic ovarian tumor types. Medical records were abstracted for 678 eligible patients on lifestyle, medical and cancer treatment, and review of pathology slides was performed for 605 patients. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazard models adjusted for age at diagnosis, race, stage and residual disease. RESULTS: Among patients receiving adjuvant chemotherapy (N=432), current smoking was significantly associated with shorter duration of overall (OS; HR, 8.56; 95% CI, 1.50-48.7) and progression-free (PFS; HR, 5.74; 95% CI, 1.05-31.4) survival from mucinous ovarian cancer only. There was no significant association between neoadjuvant chemotherapy and survival. However, among patients receiving neoadjuvant chemotherapy (N=44), current smokers had shorter PFS (HR, 4.32; 95% CI, 1.36-13.8; N=32 progressed/9 censored events) compared to never smokers, but the HRs were not statistically different across smoking categories (P interaction=0.87). CONCLUSIONS: Adverse associations were observed between smoking status and OS or PFS among patients with mucinous ovarian cancer receiving adjuvant chemotherapy. No significant effect was found from neoadjuvant chemotherapy on PFS overall; however, smoking may modify this association. Although needing replication, these findings suggest that patients may benefit from smoking cessation interventions prior to treatment with chemotherapy.