Modelling bispecific monoclonal antibody interaction with two cell membrane targets indicates the importance of surface diffusion

We have developed a mathematical framework for describing a bispecific monoclonal antibody interaction with two independent membrane-bound targets that are expressed on the same cell surface. The bispecific antibody in solution binds either of the two targets first, and then cross-links with the second one whilst on the cell surface, subject to rate-limiting lateral diffusion step within the lifetime of the monovalently engaged antibody-antigen complex. At experimental densities, only a small fraction of the free targets is expected to lie within the reach of the antibody binding sites at any time. Using ordinary differential equation and Monte Carlo simulation-based models, we validated this approach against an independently published anti-CD4/CD70 DuetMab experimental data set. As a result of dimensional reduction, the cell surface reaction is expected to be so rapid that, in agreement with the experimental data, no monovalently bound bispecific antibody binary complexes accumulate until cross-linking is complete. The dissociation of the bispecific antibody from the ternary cross-linked complex is expected to be significantly slower than that from either of the monovalently bound variants. We estimate that the effective affinity of the bivalently bound bispecific antibody is enhanced for about four orders of magnitude over that of the monovalently bound species. This avidity enhancement allows for the highly specific binding of anti-CD4/CD70 DuetMab to the cells that are positive for both target antigens over those that express only one or the other We suggest that the lateral diffusion of target antigens in the cell membrane also plays a key role in the avidity effect of natural antibodies and other bivalent ligands in their interactions with their respective cell surface receptors

Adherence to low-carbohydrate diet in relation to gastric cancer : Findings from a case-control study in Iran

This study examined the association between adherence to low carbohydrate diet (LCD) and risk of gastric cancer (GC). This hospital-based case-control study was conducted in Iran Cancer Institute, Tehran, Iran between 2010 and 2012. Totally, 178 patients with GC and 276 apparently healthy controls participated in this study. Cases were histo-pathologically confirmed GC patients aged ≥40 years diagnosed with GC in the last year. Dietary intakes were assessed using a validated 146-item Diet History Questionnaire. We computed the LCD score trough the protocol explained by Halton. Patients with GC were older (60.8 vs. 53.2 years, P < 0.001) and more likely to be male (74.2 vs. 63.8%, P = 0.02), married (97.8 vs. 86.6%, P < 0.001) and illiterate (62.4% vs. 26.1%, P < 0.001) than controls. Before adjusting for covariates, adherence to LCD-diet was not associated with risk of GC [odds ratio (OR) 1.31; 95% confidence interval (CI) 0.82-2.09 for highest vs. lowest tertile; Ptrend< 0.26]. Adjustments for several potential confounders including H-pylori infection and BMI, participants in the highest tertile of LCD score were 7% more likely to have GC than those in the lowest tertile; however, it was not statistically significant (OR 1.07; 95% CI 0.59-1.95 for highest vs. lowest tertile; Ptrend< 0.79). No significant association was also seen between adherence to animal- or vegetable-based LCD diet and risk of GC. In conclusion, we failed to find any evidence on the association between consumption of LCD and odds of GC. Further studies, in particular of prospective design, are required to confirm these findings.acceptedVersionPeer reviewe

Human Papillomavirus and Risk of Head and Neck SquamousCell Carcinoma in Iran

Human papillomavirus (HPV) causes a subset of head and neck squamous cell carcinoma (HNSCC). Knowledge of determinants of α-, β-, and γ-HPVs types in the oral cavity is required for a better understanding of HNSCC development. Oral rinse samples of 498 HNSCC cases and 242 controls from the IROPICAN study—a large multicenter case-control study in Iran—were screened for 21 α-HPV, 46 β-HPVs, and 52 γ-HPVs using bead-based HPV genotyping assays. α-HPVs were detected only in 1.2% of the patients and 2.9% of the controls from which HPV16 was the most prevalent type among participants. β-HPVs were detected in 43.8% of the patients and 38.6% of the controls where the lip and oral cavity (45.5%) had the highest positivity. Values for γ-HPV prevalence in patients and controls were 26.1% and 24.7%, respectively. The highest percentage of γ-HPV positivity was found in the larynx (30.4%). Concerning the β genus, HPV23 and HPV38 were the most prevalent types among the patients and controls, respectively. For the γ genus, SD2 in cases and HPV134 in controls were the most prevalent types. Overall, detection of α-HPVs (aOR, 0.40; 95% CI = 0.1 to 1.2; P = 0.11), β-HPVs (aOR, 1.9; 95% CI = 0.9 to 1.6; P = 0.29), and γ-HPVs infections (aOR, 1.04; 95% CI = 0.7 to 1.5; P = 0.83) was not associated with the HNSCC development. Our data did not suggest an HPV-related etiology for HNSCC pathogenesis. Nonetheless, this study provides novel insights into the diversity of β-, and γ-HPVs in different HNSCC anatomical subsites

Patterns of Nutrient Intake in Relation to Gastric Cancer : A Case Control Study

Gastric Cancer (GC) is the most common cancer among Iranian men. We conducted a case-control study to investigate the association between patterns of nutrient intake and the risk of GC in Iran. We enrolled 178 GC patients and 271 controls matched for age and sex. We collected dietary intakes using a validated diet history questionnaire. We performed factor analysis on 28 nutrients using multivariate logistic regression models on tertiles of factor scores and estimated odds ratios (OR) and 95% confidence intervals (95% CI). We identified three nutrient patterns. The first pattern included pantothenic acid, riboflavin, zinc, animal protein, and calcium. Selenium, thiamin, carbohydrate, vegetable protein, niacin and low intake of vitamin E loaded the second pattern, and the third pattern was abundant in fiber, carotene, vitamin C and A. We found no significant association between GC and any of the dietary patterns. However, in the first patterns, men in the highest tertile had significantly higher odds of GC than the lowest (OR = 2.15, 95% CI: 1.13–4.09, p trend = 0.02). A dietary pattern loaded by animal products may increase the risk of GC among Iranian men. Larger studies are required to approve these findings in overall and in different subgroups. Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.1931697.acceptedVersionPeer reviewe

Association between gastric cancer and the intake of different types of iron and meats

Background: Heme and non-heme irons are two forms of iron in the diet. Few studies have evaluated the association between heme iron intake and the risk of gastric cancer (GC). We aimed to investigate the association between heme, non-heme and total iron intake and risk of GC in Iran. Methods: In a hospital-based case–control study, nutritionists interviewed 178 pathologically confirmed GC patients and 276 controls using a valid Diet History Questionnaire. Multiple logistic regression model was used to estimate Odds Ratios (OR) and 95% Confidence Intervals (CIs) for iron intake and risk of GC. Results: Subjects in the highest tertile of total iron intake were 46% less likely to get GC than those in the lowest (OR = 0.54, 95% CI: 0.32–0.92), however, the associations were not significant for intake of heme and non-heme iron. The risk of GC in the highest tertile of total meat intake was 2.51 times higher than the lowest. We found significant associations between GC and chicken (OR = 2.95; 95% CI: 1.66–5.22) and fish intake (OR = 1.89; 95% CI: 1.09–3.27), However, we found no associations between the risk of GC and intake of red meat, salted fish, and liver. Conclusion: Total iron intake was associated with a lower risk of GC which could be partly due to the high prevalence of anemia in Iran. Although, we could not find any significant association between the risk of GC and the intake of heme and non-hem iron among the Iranian population.publishedVersionPeer reviewe

Vitamins and Stomach Cancer : A Hospital Based Case-Control Study in Iran

Background: This study investigated the association between vitamins intakes and risk of gastric cancer (GC) among Iranian population. Methods: In this hospital-based case-control study, 178 pathologically confirmed GC patients and 276 healthy controls were interviewed to answer a valid diet history questionnaire. Unconditional logistic regression, in which potential confounders were taken into account, was applied to determine the association of vitamin intakes and odds of GC in total population and in stratums of body mass index (BMI), helicobacter pylori (H-pylori) infection, and smoking. Results: GC was directly associated with vitamin D (OR 1.59; CI 95% 1.07, 2.36) and cobalamin (OR 1.25; CI 95% 1.08, 1.44). Thiamin (OR 0.50; 95%CI 0.30, 0.83), pantothenic acid (OR 0.71; 95%CI 0.58, 0.87), folate (OR 0.99; 95%CI 0.99, 0.99) and vitamin E (OR 0.98; 95%CI 0.96, 0.99) were inversely associated with GC. In 231 H-pylori infected participants, consumption of thiamin (OR 0.3; 95% CI 0.59, 0.86), pyridoxine (OR 0.52; 95%CI 0.31, 0.85), and folate (OR 0.99; 95%CI 0.99, 0.99) reduced GC risk. In H-pylori negative participants, only vitamin E (OR 0.96; 95%CI 0.93, 0.99) reduced the risk and vitamin D (OR 1.99; 95%CI 1.18, 3.36), riboflavin (OR 1.91; 95%CI 1.37, 2.66), pantothenic acid (OR 1.34; 95%CI 1.13, 1.64), biotin (OR 1.03; 95%CI 1.01, 1.05), and cobalamin (OR 1.36; 95%CI 1.13, 1.64) increased the risk. In BMI stratums, only vitamin D (OR 1.81; 95%CI 1.07, 3.08) was associated with the risk of GC among normal weight participants. Vitamin E was associated with lower risk of GC in ever smokers (OR 0.97; 95%CI 0.95, 0.99) and thiamin (OR 0.41; 95%CI 0.19, 0.86) and niacin (OR 0.93; 95%CI 0.87, 0.99) were associated with lower risk in never smokers. Positive associations were observed by increasing vitamin D (OR 2.08; 95%CI 1.12, 3.85) and cobalamin (OR 1.33; 95%CI 1.08, 1.65) in never smokers. Conclusion: This study provided support for a possible protective effect of vitamin E, thiamin, pantothenic acid, and folate on GC risk. Vitamin D and cobalamin intake increased the risk.publishedVersionPeer reviewe

Opium use and risk of bladder cancer: a multi-centre case-referent study in Iran

Background Bladder cancer (BC) is the 10th most common type of cancer worldwide and the fourth most common type of cancer in Iran. Opium use is considered as one of the risk factors for BC. We aim to assess the association between various parameters of opium use, which in Iran is mainly ingested or smoked in various forms, and the risk of BC. Method In this multi-centre case-referent study in Iran, 717 BC cases and 3477 referents were recruited to the study from May 2017 until July 2020. Detailed histories of opium use (duration, amount, frequency) and potential confounders were collected by trained interviewers. Multivariable unconditional logistic regression models were used to measure adjusted odds ratio (OR) and 95% confidence intervals (CI). The ORs were adjusted for age, gender, place of residence and pack-years of cigarette smoking. Results Regular opium consumption was associated with an increased risk of BC (OR 3.5, 95% CI: 2.8, 4.3) compared with subjects who never used opium. Compared with continuous users, the risk decreased to one-third for those who stopped opium more than 10 years ago. The adjusted OR for those who used both crude opium (teriak) and opium juice was 7.4 (95% CI: 4.1, 13.3). There was a joint effect of opium and tobacco (OR for users of both opium and tobacco 7.7, 95% CI: 6.0, 9.7). Conclusions Regular opium use is associated with an approximately 4-fold risk for BC. The OR decreases along with the increasing time since stopping opium use

Geographic distribution and time trends of water-pipe use among Iranian youth and teenage students : A meta-analysis and systematic review

Water-pipe tobacco smoking is harmful to health, yet its rate of prevalence remains uncertain. Recent evidence has shown that the prevalence of water-pipe smoking among students is higher than in the general population. In this study, a systematic review of related literature on water-pipe use was conducted, and for this purpose, 76 articles were examined in the study. In this vein, geographic distribution and time trends of water-pipe consumption in Iran were considered. The results of this study showed that lifetime, last-year, and last-month prevalence of water-pipe smoking use among Iranian students were 28.78 (25.07–32.49), 20.84 (16.01–25.66), and 16.36 (11.86–20.85), respectively. The results also showed a wide variation by the region and sex in Iran. This study has shown the importance of addressing public prevention and alerting programs in schools and universities.acceptedVersionPeer reviewe

Human Papillomavirus and Risk of Head and Neck Squamous Cell Carcinoma in Iran

Human papillomavirus (HPV) causes a subset of head and neck squamous cell carcinoma (HNSCC). Knowledge of determinants of α-, β-, and γ-HPVs types in the oral cavity is required for a better understanding of HNSCC development. Oral rinse samples of 498 HNSCC cases and 242 controls from the IROPICAN study-a large multicenter case-control study in Iran-were screened for 21 α-HPV, 46 β-HPVs, and 52 γ-HPVs using bead-based HPV genotyping assays. α-HPVs were detected only in 1.2% of the patients and 2.9% of the controls from which HPV16 was the most prevalent type among participants. β-HPVs were detected in 43.8% of the patients and 38.6% of the controls where the lip and oral cavity (45.5%) had the highest positivity. Values for γ-HPV prevalence in patients and controls were 26.1% and 24.7%, respectively. The highest percentage of γ-HPV positivity was found in the larynx (30.4%). Concerning the β genus, HPV23 and HPV38 were the most prevalent types among the patients and controls, respectively. For the γ genus, SD2 in cases and HPV134 in controls were the most prevalent types. Overall, detection of α-HPVs (aOR, 0.40; 95% CI = 0.1 to 1.2; P = 0.11), β-HPVs (aOR, 1.9; 95% CI = 0.9 to 1.6; P = 0.29), and γ-HPVs infections (aOR, 1.04; 95% CI = 0.7 to 1.5; P = 0.83) was not associated with the HNSCC development. Our data did not suggest an HPV-related etiology for HNSCC pathogenesis. Nonetheless, this study provides novel insights into the diversity of β-, and γ-HPVs in different HNSCC anatomical subsites. IMPORTANCE Infection with human papillomavirus (HPV) is responsible for a subset of neck squamous cell carcinoma (HNSCC), but knowledge of the prevalence of and risk factors for oral HPV infection, especially cutaneous types in Iran, remains unknown. In a large retrospective study, the authors used a sensitive assay for the detection of α-, β-, and γ-HPVs in oral rinse samples of HNSCC and matched controls. They find that the α-HPV contribution to HNSCC in Iran is lower than global prevalence. High-risk α-HPVs or cutaneous β- and γ-HPVs were not associated with the HNSCC development. Besides, this study provides novel insights into the diversity of β- and γ-HPVs in different HNSCC anatomical subsites.publishedVersionPeer reviewe

Dietary total antioxidant capacity and head and neck cancer: a large case-control study in Iran

BackgroundData on the association between head and neck cancer (HNC) and dietary factors are inconclusive. No study has so far investigated the association between dietary total antioxidant capacity (dTAC) and HNC concerning interactions with other risk factors.MethodPathologically confirmed new diagnosed HNC patients were included in this study. The control group was healthy hospital visitors who were frequently matched with patients on age (5 years interval), gender, and province of residence. Trained interviewers administered a validated Food Frequency Questionnaire (FFQ) to assess the participants’ food intake 1 year before the cancer diagnosis. Data on TAC scores of foods was collected by Ferric Reducing Antioxidant Power (FRAP) and Total Radical-trapping Antioxidant Parameters (TRAP) from published data. We applied logistic regression adjusted for age, sex, energy intake, socioeconomic status, province, opium use, alcohol use, physical activity, and dental health. We also studied the interaction of dTAC with tobacco smoking status, and opium use on the risk of HNC.ResultsWe recruited 876 HNC patients and 3,409 healthy controls. We observed a significant decrease in the odds of HNC with increasing dTAC scores. The OR of HNC for the third vs. the first tertile was 0.49 (95%CI 0.39–0.61) for FRAP and 0.49 (95%CI 0.39–0.62) for TRAP. Both dTAC scores were inversely associated with lip and oral (T3 ver. T1 OR = 0.51; 95%CI 0.36–0.71 for FRAP and OR = 0.59; 95% CI 0.44–0.82 for TRAP) and larynx (T3 ver. T1 OR = 0.43; 95%CI 0.31–0.61 for FRAP and OR = 0.38; 95% CI 0.26–0.55 for TRAP) cancers. There was no interaction between tobacco smoking, opium use; and TRAP or FRAP on the risk of HNC.ConclusionAn antioxidant-rich diet in terms of FRAP or TRAP could decrease the risk of HNC and its subtypes