Conversational artificial intelligence: the interface with the patient concerns inventory.

The patient concerns inventory (PCI) allows patients to highlight the issues they would like to discuss at their outpatient consultation. It improves patient-clinician communication and has proven benefits. While the PCI is effective, patient experiences could be improved with better access to it and the ability to more easily and frequently express their concerns. This, of course, is in the context of ever-increasing healthcare challenges and limited resources. Use of conversational artificial intelligence (CAI) represents an opportunity to improve information flow between patients and professionals remote from the consultation. This paper highlights the potential for CAI to provide an 'always-on' platform, using natural language interface technology and based on the PCI, which patients can access via their mobile devices. We also discuss potential pitfalls and concerns, along with outlining a current clinical trial assessing, in the first instance, usability of this technology.

Alcohol, tobacco, and marijuana consumption is associated with increased odds of same-day substance co- and tri-use.

BACKGROUND: Little is known about event-level patterns of marijuana co- or tri-use with alcohol and tobacco. Thus, the study goal was to examine patterns of same-day alcohol, cigarette, and marijuana co- and tri-use at the individual level in non-treatment-seeking alcohol users. METHODS: Participants (N = 551) completed an in-person interview for alcohol, cigarette, and marijuana use over the previous 30 days, and the event-level substance use patterns of n = 179 participants who reported using each of these substances at least once per month were analyzed. RESULTS: The use of alcohol, marijuana, or cigarettes independently increased the probability of subsequent, simultaneous co-use of one of the two remaining substances. The co-use of alcohol with cigarettes and marijuana with cigarettes produced generally additive effects on the odds of same day tri-use of marijuana and alcohol, respectively. Conversely, the co-use of alcohol and marijuana produced sub-additive effects on likelihood of cigarette use. Sex moderated several of the observed patterns of co- and tri-use: the relationship between alcohol or cigarette use predicting marijuana co-use was stronger in men, whereas the observed additive relationships between drug co-use leading to tri-use was stronger in women. CONCLUSIONS: The presented results may aid in the understanding of how simultaneous co-use of marijuana with alcohol and/or tobacco relates to the etiology, maintenance, and treatment of comorbid and trimorbid substance use disorder. Replication and extension of the results in treatment seeking populations using more fine-grained analysis approaches, e.g. ecological momentary assessment, is needed.

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance.

Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC, potentially in combination with chemotherapies and agents targeting the Akt pathway.

Prospective study of early bereavement on psychological and behavioural cardiac risk factors.

BACKGROUND: Increasing evidence supports the role of emotional stress in the onset of cardiovascular disease. Although bereavement is a major emotional stress with both acute and more long-term features, the mechanism of its association with cardiovascular risk is not well understood, in particular because of limited studies of acute bereavement. The aim of the study was to identify psychological and behavioural changes in acute bereavement and potential modifiers of these changes. METHODS: Bereaved (n= 62) and non-bereaved individuals (n= 50) were evaluated within 2 weeks and at 6 months following loss using the Centre for Epidemiologic Studies -- Depression, Spielberger State Anxiety and Anger, Social Support Questionnaire and changes in appetite, cigarette and alcohol consumption, cortisol and lipids. RESULTS: Compared with non-bereaved, acutely bereaved had increased symptoms of depression (26.7 +/- 1.7 vs 5.9 +/- 0.7, P < 0.001), anxiety (47.4 +/- 2.0 vs 28.2 +/- 1.4, P < 0.001) and anger (median 16.0 vs 15.0, P < 0.001). Greater depressive symptoms were associated with being unprepared for the death, decreased sleep duration and younger age. Acutely, bereaved slept less than non-bereaved (5.8 +/- 0.2 vs 7.2 +/- 0.2 h, P < 0.001). Reduced sleep time was associated with increased anger and depression and decreased satisfaction with social support. Compared with the non-bereaved, the acutely bereaved had higher cortisol (median 306 vs 266, P= 0.003), reduced appetite (P < 0.001) and lower total cholesterol (median 4.9 vs 5.4, P= 0.006) and low-density lipoprotein (median 2.4 vs 2.9, P < 0.001). CONCLUSION: These results offer insight into the psychological, behavioural and physical changes that may contribute to cardiovascular risk in bereavement.

Questionnaire or objective assessment for studying exposure to tobacco smoke among asthmatic and healthy children: The French VESTA Study.

BACKGROUND: The underreporting of environmental tobacco smoke (ETS) exposure by parents of study children may depend on the instrument used and population studied, underlining the need for questionnaire validation in specific study settings. This study explores the validity of parent-reported ETS exposure in a French multicenter study on asthma. METHODS: The study population was composed of 313 children ages 4 to 14 years. Exposure to ETS was evaluated both by questionnaires on recent ETS exposure and by assessment of urinary cotinine by an enzyme immunoassay. RESULTS: According to parents' reports, about one-third of children were exposed to ETS within the past 2 days before cotinine measurement, and on average 14.9 +/- 15.4 cigarette-equivalent were smoked in their homes. The mean urinary cotinine was 435 +/- 530 nmol/mol creatinine and increased with the reported number of cigarette-equivalents smoked at home but it did not differ between children registered as being exposed to 1-10 cigarettes and children registered as unexposed. Agreement between questionnaire and urinary cotinine was moderate to poor according to our correlation coefficient (0.22) and kappa coefficient (0.09). CONCLUSION: These results show that our questionnaire is not discriminating enough to distinguish between nonexposure and mild exposure, but reveals gradients of higher exposure.

Design and synthesis of potent and selective inhibitors of integrin VLA-4.

The synthesis and identification of a novel series of inhibitors of integrin VLA-4 are described. Their in vitro activity and selectivity against closely related integrins are also presented.

Hydrophilic, pro-drug analogues of T138067 are efficacious in controlling tumor growth in vivo and show a decreased ability to cross the blood brain barrier.

The novel anticancer compound T138067 is an irreversible inhibitor of tubulin polymerization. Amides 3-6 were synthesized using standard methodologies and determined to be significantly less lipophilic than T138067 based on logP calculations. Tubulin polymerization and [(3)H]-T138067 competition assays revealed that these amides are pro-drugs for parent aniline 2. Amides 3-5 showed no detectable signs of crossing the blood brain barrier, while amide 6 was found in extremely small amounts (12 ng/g of brain tissue). Aniline 2, which was formed in vivo from these amides, was found in significantly smaller amounts (approximately 20 to >5000 times) in the brain than when 2 was administered directly. The in vivo efficacy of amide 6 approached that of T138067 and was better tolerated when administered to athymic nude mice bearing MX-1 human mammary tumor xenografts.

The clinical significance of atypical squamous cells of undetermined significance: a laboratory audit of cervical reporting.

AIM: To determine the outcomes in women diagnosed with 'Atypical Squamous Cells of Undetermined Significance' (ASCUS) on cervical smears. METHODS: All diagnoses of ASCUS on cervical smears made at Southern Community Laboratories (SCL) in Christchurch in 1996 were retrieved from the SCL database and correlated with all available previous and subsequent smear and biopsy results from these patients. The outcome was reported as the most significant (highest grade) cervical smear or biopsy over the following two year period. RESULTS: 278 women had smear results of ASCUS in 1996, reflecting 2.3% of total cervical smear diagnoses at SCL (Christchurch) for that period. Follow-up was available for 260 (94%). 61% had benign (normal or inflammatory) changes, 6% had persistent ASCUS (smear only), 18% had a Low Grade Squamous Intraepithelial Lesion (LSIL), and 15% had a High Grade Squamous Intraepithelial Lesion (HSIL). All women with ASCUS who subsequently developed HSIL had persistent abnormal smears. CONCLUSIONS: An ASCUS smear result indicates a group of women who have an increased risk for detection of HSIL. The effectiveness of routine Pap smears for detection of cervical cytologic abnormality is confirmed.

Comparison of micronutrients in patients having had panproctocolectomy and either ileal pouch anal anastomosis or Brooke ileostomy for chronic ulcerative colitis (UC).

OBJECTIVE: Patients having panproctocolectomy undergo major metabolic changes. A recent study suggested that patients who have had a panproctocolectomy and ileal pouch-anal anastomosis (IPAA) may be trace element-deficient, while other recent evidence has suggested a gradual decrease in vitamin B12. This study was undertaken to compare patients who had a panproctocolectomy for UC in combination with either an IPAA or a Brooke ileostomy (BI), and to determine whether the type of surgery post-proctocolectomy influences the absorption of trace elements, as well as comparing the levels after both operations with the normal population values. PATIENTS AND METHODS: One hundred randomly selected patients who had had a panproctocolectomy for UC (50 IPAA, 50 BI) were invited to take part in the study by letter. The patients who consented had blood taken for haemoglobin, serum iron, ferritin, serum folate, red cell folate, vitamin B12, insulin-like growth factor-1 (IGF-1), albumin, and the trace elements copper, magnesium, manganese, selenium, and zinc. RESULTS: Of the 100 patients, 46 consented to participate in the study (23 IPAA, 23 BI). The age of the BI group was significantly higher than those of the IPAA group (mean age IPAA 44 years, BI 52 years, P < 0.05). There was no significant difference between the two groups with respect to time since operation, mean levels of haemoglobin, iron indices, albumin, serum and red cell folate, vitamin B12, or any of the trace elements examined. Plasma IGF-1 was higher in the IPAA group, but this was no longer significant when adjusted for age. CONCLUSION: No difference was found in trace element status in patients who had had a panproctocolectomy for UC with either an IPAA or BI. Furthermore, no difference existed between these two groups.

Fas ligand and Fas receptor are coexpressed in normal human esophageal epithelium: a potential mechanism of apoptotic epithelial turnover.

Fas (CD95/Apo-1) receptor (FasR) is a cell-surface receptor that mediates apoptotic cell death upon triggering by Fas ligand (FasL). We sought to determine whether normal human esophageal epithelial cells express FasL and/or FasR and whether their localization is consistent with a role in the turnover of normal esophageal epithelium. Normal esophageal epithelium was immunohistochemically positive for FasL in upper prickle cell layers and in mature squamous cells, but the proliferative basal layer was negative. FasL mRNA was detected in the same epithelial cell layers by in situ hybridization. Co-localization of FasL mRNA and protein therefore confirmed that FasL expression is induced in esophageal epithelial cells as they reach terminal differentiation. FasR was immunohistochemically detected throughout the esophageal epithelium. Positive TUNEL (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling) staining confirmed cell death of the FasL and FasR coexpressing mature epithelial cells. CD45-positive immunocytes were notably absent from FasL-expressing upper epithelial layers. The findings are consistent with a contributory role for Fas-mediated autocrine suicide or paracrine fratricide in the apoptotic turnover of normal esophageal epithelium.

Novel halogenated sulfonamides inhibit the growth of multidrug resistant MCF-7/ADR cancer cells.

In this report, we describe the synthesis of halogenated benzenesulfonamide compounds and their ability to inhibit the growth of HeLa, MCF-7 and MCF-7/ADR tumor cells in vitro. The multidrug resistance (MDR) phenotype of certain cells does not affect their sensitivity to these compounds. These agents belong to a family of compounds previously shown to bind irreversibly to cysteine-239 of beta-tubulin. Consistent with this mechanism of action, the cytotoxicities of these compounds appear to correlate with their ability to undergo nucleophilic aromatic substitution.

Oxidative turnover of soybean root glutamine synthetase. In vitro and in vivo studies

Glutamine synthetase (GS) is the key enzyme in ammonia assimilation and catalyzes the ATP-dependent condensation of NH3 with glutamate to produce glutamine. GS in plants is an octameric enzyme. Recent work from our laboratory suggests that GS activity in plants may be regulated at the level of protein turnover (S.J. Temple, T.J. Knight, P.J. Unkefer, C. Sengupta-Gopalan [1993] Mol Gen Genet 236: 315-325; S.J. Temple, S. Kunjibettu, D. Roche, C. Sengupta-Gopalan [1996] Plant Physiol 112: 1723-1733; S.J. Temple, C. Sengupta-Gopalan [1997] In C.H. Foyer, W.P. Quick, eds, A Molecular Approach to Primary Metabolism in Higher Plants. Taylor & Francis, London, pp 155-177). Oxidative modification of GS has been implicated as the first step in the turnover of GS in bacteria. By incubating soybean (Glycine max) root extract enriched in GS in a metal-catalyzed oxidation system to produce the.OH radical, we have shown that GS is oxidized and that oxidized GS is inactive and more susceptible to degradation than nonoxidized GS. Histidine and cysteine protect GS from metal-catalyzed inactivation, indicating that oxidation modifies the GS active site and that cysteine and histidine residues are the site of modification. Similarly, ATP and particularly ATP/glutamate give the enzyme the greatest protection against oxidative inactivation. The roots of plants fed ammonium nitrate showed a 3-fold increase in the level of GS polypeptides and activity compared with plants not fed ammonium nitrate but without a corresponding increase in the GS transcript level. This would suggest either translational or posttranslational control of GS levels.

Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer.

BACKGROUND: Despite being immunogenic, gastric cancers overcome antitumour immune responses by mechanisms that have yet to be fully elucidated. Fas ligand (FasL) is a molecule that induces Fas receptor mediated apoptosis of activated immunocytes, thereby mediating normal immune downregulatory roles including immune response termination, tolerance acquisition, and immune privilege. Colon cancer cell lines have previously been shown to express FasL and kill lymphoid cells by Fas mediated apoptosis in vitro. Many diverse tumours have since been found to express FasL suggesting that a "Fas counterattack" against antitumour immune effector cells may contribute to tumour immune escape. AIM: To ascertain if human gastric tumours express FasL in vivo, as a potential mediator of immune escape in stomach cancer. SPECIMENS: Thirty paraffin wax embedded human gastric adenocarcinomas. METHODS: FasL protein was detected in gastric tumours using immunohistochemistry; FasL mRNA was detected in the tumours using in situ hybridisation. Cell death was detected in situ in tumour infiltrating lymphocytes using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). RESULTS: Prevalent expression of FasL was detected in all 30 resected gastric adenocarcinomas examined. In the tumours, FasL protein and mRNA were co-localised to neoplastic gastric epithelial cells, confirming expression by the tumour cells. FasL expression was independent of tumour stage, suggesting that it may be expressed throughout gastric cancer progression. TUNEL staining disclosed a high level of cell death among lymphocytes infiltrating FasL positive areas of tumour. CONCLUSIONS: Human gastric adenocarcinomas express the immune downregulatory molecule, FasL. The results suggest that FasL is a prevalent mediator of immune privilege in stomach cancer.

The Fas counterattack in vivo: apoptotic depletion of tumor-infiltrating lymphocytes associated with Fas ligand expression by human esophageal carcinoma.

Various cancer cell lines express Fas ligand (FasL) and can kill lymphoid cells by Fas-mediated apoptosis in vitro. FasL expression has been demonstrated in several human malignancies in vivo. We sought to determine whether human esophageal carcinomas express FasL, and whether FasL expression is associated with increased apoptosis of tumor-infiltrating lymphocytes (TIL) in vivo, thereby contributing to the immune privilege of the tumor. Using in situ hybridization and immunohistochemistry, respectively, FasL mRNA and protein were colocalized to neoplastic esophageal epithelial cells in all esophageal carcinomas (squamous, n = 6; adenocarcinoma, n = 2). The Extent of FasL expression was variable, with both FasL-positive and FasL-negative neoplastic regions occurring within tumors. TIL were detected by immunohistochemical staining for the leukocyte common Ag, CD45. FasL expression was associated with a mean fourfold depletion of TIL when compared with FasL-negative areas within the same tumors (range 1.6- to 12-fold, n = 6,p < 0.05). Cell death of TIL was detected by dual staining of CD45 (immunohistochemistry) and DNA strand breaks (TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling). There was a mean twofold increase in detectable cell death among TIL in FasL-positive areas compared with FasL-negative areas (range 1.6- to 2.4-fold, n = 6, p < 0.05). In conclusion, we demonstrate a statistically significant, quantitative reduction of TIL concomitant with significantly increased TIL apoptosis within FasL-expressing areas of esophageal tumors. Our findings suggest Fas-mediated apoptotic depletion of TIL in response to FasL expression by esophageal cancers, and provide the first direct, quantitative evidence to support the Fas counterattack as a mechanism of immune privilege in vivo in human cancer.

Fas ligand expression in primary colon adenocarcinomas: evidence that the Fas counterattack is a prevalent mechanism of immune evasion in human colon cancer.

Fas ligand (FasL) kills sensitive Fas receptor (FasR)-bearing cells by inducing apoptosis. FasL expressed by non-lymphoid cells within the eye and the testis mediates immune privilege by inducing apoptosis of Fas-sensitive infiltrating pro-inflammatory immune effector cells. It has previously been demonstrated by the present authors that the colon cancer cell SW620 expresses FasL and can kill lymphoid cells by Fas-mediated apoptosis in vitro. This 'Fas counterattack' was subsequently confirmed by others as a potential mechanism of immune privilege in various malignancies. The aim of the present study was to ascertain the prevalence of FasL expression in human colon cancer and to confirm that neoplastic colonic epithelial cells express FasL in vivo. The study of FasL expression by colon cancer cell lines was extended: it was shown that seven of eight colon adenocarcinoma cell lines expressed FasL mRNA, using reverse transcription-polymerase chain reaction (RT-PCR). Prevalent expression of FasL was confirmed in vivo: all the resected colonic tumours examined (31/31) were found to express FasL. In the tumours, FasL were co-localized to neoplastic colonic epithelial cells, using immunohistochemistry and in situ hybridization, respectively. FasL expression was independent of Dukes' stage, suggesting that it may occur throughout colon cancer progression. These results suggest that FasL is a common mediation of immune privilege in colon cancer.

Novel antineoplastic agents with efficacy against multidrug resistant tumor cells.

A novel series of pentafluorobenzenesulfonamides has been shown to inhibit the growth of a variety of human tumor cell lines. Among the cell types against which these agents were evaluated were the multidrug resistant (MDR) cell lines MCF-7/ADR and P388/ADR. The cytotoxic activity of members of this series of compounds was not affected by the multidrug resistant pump in MCF-7/ADR or P388/ADR cells.