bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5284: M1231 is a bispecific anti-MUC1xEGFR antibody-drug conjugate designed to treat solid tumors with MUC1 and EGFR co-expression
Authors: Knuehl Christine , Toleikis Lars , Dotterweich Julia , Ma Jianguo , Kumar Seema , Ross Edith , Wilm Claudia , Schmitt Martina , Grote Hans Juergen , Amendt Christiane
Published: June 2022

Mucin 1 (MUC1) and epidermal growth factor receptor (EGFR) are co-expressed at high prevalence in multiple cancer indications such as non-small cell lung cancer (NSCLC), esophageal squamous cell carcinoma (ESCC), head and neck squamous cell carcinoma, triple negative breast cancer and ovarian cancer. Tumor-associated MUC1 is hypoglycosylated and exposes peptide epitopes within its extracellular domain, which are not accessible to antibodies in normal epithelial tissue. MUC1 co-localizes with EGFR as a result of loss of cell polarity in tumor cells. M1231 is a bispecific antibody-drug conjugate (ADC) based on a SEED (strand-exchange engineered domain)-antibody scaffold targeting tumor-associated MUC1 and EGFR. Sutro Biopharma’s cell free expression system Xpress CF+™ enables incorporation of non-natural amino acids at precise positions in the SEED-antibody for site-specific linker-payload conjugation. The cytotoxic payload of M1231 (SC209) is a hemiasterlin-related microtubule inhibitor. The cleavable linker (ValCit-PABA) maintained ADC stability in human plasma in vitro, ensuring low systemic payload release. Pre-clinical activity of M1231 was assessed in vitro in cancer cell lines and in vivo in NSCLC and ESCC patient-derived xenograft (PDX) models. M1231 inhibited tumor cell viability in vitro at sub-nanomolar IC50 values. The bispecific MUC1xEGFR antibody has demonstrated superior internalization and lysosomal trafficking compared to monospecific bivalent antibodies. Efficient ADC uptake resulted in superior antitumor activity of M1231 in PDX models compared to monospecific bivalent ADCs. M1231 demonstrated durable and dose-dependent antitumor activity in PDX models. Strong antitumor activity with complete regression was observed in NSCLC and ESCC PDX models following a single treatment of M1231. M1231 antitumor activity was associated with high target expression in NSCLC PDX models and was observed across a range of target expression levels in ESCC models. In summary, efficient payload delivery to tumor cells and strong antitumor activity of M1231 indicate that M1231 may have the potential to deliver an efficacy benefit to patients with tumors co-expressing MUC1 and EGFR.

Citation Format: Christine Knuehl, Lars Toleikis, Julia Dotterweich, Jianguo Ma, Seema Kumar, Edith Ross, Claudia Wilm, Martina Schmitt, Hans Juergen Grote, Christiane Amendt. M1231 is a bispecific anti-MUC1xEGFR antibody-drug conjugate designed to treat solid tumors with MUC1 and EGFR co-expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5284.
Abstract 5426: Down-regulation of cancer metabolism enhances radiosensitivity by impairing the heat shock response
Authors: Schwab Melissa , Thunborg Katharina , Azimzadeh Omid , von Toerne Christine , Shevtsov Maxim , Zdralevic Masa , Pouyssegur Jacques , Renner Kathrin , Kreutz Marina , Vaupel Peter , Multhoff Gabriele
Published: June 2022

Therapy (radiation) resistance can, inter alia, be caused by an increased lactate dehydrogenase (LDH) activity, elevated concentrations of the oncometabolite lactate and an overexpression of anti-apoptotic heat shock proteins (HSPs). In this study we aimed to break radioresistance by targeting the cancer metabolism. We could show, for the first time, that the lactate metabolism and heat shock response are co-regulated in two cancer cell systems (murine B16F10 melanoma cells, human LS174T colorectal adenocarcinoma cells). A CRISPR/Cas9 induced double knockout of LDHA/B (LDH−/−) as well as a pharmacological inhibition of LDH by Oxamate or GNE-140 reduces tumor growth, ROS production and synthesis of different HSPs, including Hsp90, Hsp70 and Hsp27. Moreover, the membrane Hsp70 density was significantly reduced on tumor cells after inhibition of the LDH activity as a consequence of a down-regulated lipid metabolism affecting the Hsp70-anchoring, tumor-specific glycosphingolipid Gb3. Our results demonstrate that influencing cancer metabolism increases radiation sensitivity by an impairment of the stress response. Since presently available LDH inhibitors have a low stability and high toxicity in vivo, we are currently investigating more potent LDH inhibitors with a beneficial safety profile. In summary, targeting the lactate metabolism provides a promising strategy to improve radiosensitivity by impairing the stress response.

Citation Format: Melissa Schwab, Katharina Thunborg, Omid Azimzadeh, Christine von Toerne, Maxim Shevtsov, Masa Zdralevic, Jacques Pouyssegur, Kathrin Renner, Marina Kreutz, Peter Vaupel, Gabriele Multhoff. Down-regulation of cancer metabolism enhances radiosensitivity by impairing the heat shock response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5426.
Abstract 5505: ADAM10-targeting CAR-T cells inhibit colon cancer cell growth in vivo
Authors: Rad Elaheh Rohani , Foeng Jade , McPeak Dylan , Tyllis Timona , Abbott Caitlin , bandara Veronika , Napoli Silvana , gundsambuu Batjargal , Barry Simon , Sadlon Timothy , McColl shaun
Published: June 2022

Chimeric antigen receptor (CAR) T cell therapy has demonstrated a high degree of efficacy in patients with hematological malignancies such as acute lymphatic leukemia. However, its efficacy in solid tumors remains to be demonstrated. There are a number of issues currently limiting therapeutic treatment of solid tumors with CAR-T cells, none more important than target antigen selection. This is a major challenge in solid tumors due to their heterogenous characteristics and the potential for off-cancer effects. ADAM10, A Disintegrin And Metalloproteinase 10, plays critical roles in a wide range of pathophysiological processes during development and inflammation. These proteolytically active multifunctional proteins act as sheddases by cleaving transmembrane-bound proteins such as growth factors, adhesion molecules and chemokine receptors, which can then contribute to migration and invasion of cancer cells. An active form of ADAM10 that has undergone a conformational change has been identified in several cancer types, particularly colorectal cancer. In this study, a novel CAR was generated based on a previously characterized cancer-specific ADAM10 antibody. ADAM-10-targeting CAR-T cells were manufactured using T cells from the peripheral blood of the healthy donors. The CAR-T cells displayed the naïve and central memory phenotype that has been shown to differentiate and proliferate within tumor microenvironments, with little expression of exhaustion markers. These CAR-T cells were capable of killing several human colorectal tumor cell lines in vitro, assessed in a bioluminescence-based cytotoxicity assay. Furthermore, treatment of NSG mice bearing human LoVo colon cancer cell tumors with ADAM-10-targeting CAR-T cells led to significant inhibition of tumor growth compared with either untransduced control T cells or PBS treatment. Overall, these data suggest that targeting ADAM-10 via CAR-T cell therapy is a promising novel avenue of treatment of colorectal cancer.

Citation Format: Elaheh Rohani Rad, Jade Foeng, Dylan McPeak, Timona Tyllis, Caitlin Abbott, Veronika bandara, Silvana Napoli, Batjargal gundsambuu, Simon Barry, Timothy Sadlon, shaun McColl. ADAM10-targeting CAR-T cells inhibit colon cancer cell growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5505.
Abstract 590: Humanized PD-1/LAG-3 mice for preclinical evaluation of combination therapy
Authors: Duan Feifei , Yang Xiaoliu , Ju Cunxiang , Zhao Jing , Gao Xiang , Chen Santi Suryani
Published: June 2022

Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily which shares homolog with CD4 and binds to MHC II with higher affinity. It is expressed on activated T cells, regulatory T cells (Tregs), natural killer cells and plasmacytoid dendritic cells, and inhibits their activation. Blocking LAG-3 activity is expected to provide therapeutic benefits in the treatment of cancer, especially when combined with PD-1 blockade. Due to the low homology between human and mouse LAG-3 and PD-1 and in order to enable increased translatability of preclinical in-vivo efficacy evaluation of immune checkpoint antibodies, we generated double humanized mice by replacing the extracellular domain of mouse LAG-3 and PD-1 with the corresponding human sequences.

Homozygous double humanized mice express chimeric LAG-3 and PD-1 at comparable levels to mouse LAG-3 and PD-1 respectively in wildtype mice. When treated with human LAG-3 antibody (anti-LAG-3) or human PD-1 antibody (anti-PD-1), CT26 tumor growth was inhibited in a dose-dependent manner, proving that both humanized proteins are functional. However, not all tumor types respond to anti-LAG-3 or anti-PD-1 the same. To identify the suitable tumor models for preclinical efficacy evaluation of anti-LAG-3 and anti-PD-1 combo therapy, we engrafted several syngeneic tumor models onto our mice. The growth of subcutaneously engrafted MC38 colon tumor was mildly inhibited by anti-PD-1, but strongly inhibited in the presence of anti-LAG-3. Similarly, B16F10 melanoma tumor showed modest growth inhibition when treated with anti-PD-1 or anti-LAG-3 separately, while combination therapy significantly repressed tumor growth. However, neither monotherapies of anti-LAG-3 and anti-PD-1 nor combination treatment effectively inhibited tumorigenesis of LLC1 derived lung cancer, indicating that this tumor is likely insensitive to PD-1 and LAG-3 blockade. Collectively, these data indicate that double humanized PD-1 and LAG-3 mice are a powerful tool to evaluate the therapeutic efficacies of anti-hPD-1 and anti-hLAG-3 treatment in different types of tumor in vivo.

Citation Format: Feifei Duan, Xiaoliu Yang, Cunxiang Ju, Jing Zhao, Xiang Gao, Santi Suryani Chen. Humanized PD-1/LAG-3 mice for preclinical evaluation of combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 590.
Abstract 5911: Soybean products consumption decreases risk for gastric cancer: Results from the Health Examinees study
Authors: Shin Woo-Kyoung , Lee Hwi-Won , Huang Dan , De la Torre Katherine , Min Sukhong , Shin Aesun , Lee Jong-koo , Lee Jung Eun , Kang Daehee
Published: June 2022

Background: Twenty percent of soy production is consumed directly by humans worldwide. However, epidemiological findings on the association between soybean products consumption and gastric cancer risk remain inconsistent. We evaluated the relationship between soybean products consumption and the risk of gastric cancer in a prospective cohort study in Korea.

Methods: This prospective cohort study included a total of 139,267 participants (men 46,953 and women 92,314) aged 40-69 years from the Health Examinees-Gem (HEXA-G) study between 2004 and 2013. Information on cancer diagnosis was retrieved from the Korea Central Cancer Registry until 31 December 2018. Multivariate hazard ratios (HRs) and 95% of confidence intervals (CIs) for the risk of gastric cancer according to the consumption of soybean products were estimated using Cox proportional hazards models with age as the time scale.

Results: A total of 884 incident cases of gastric cancer (men 480 and women 404) occurred over an average follow-up period of 9.20 years (men 9.18 years and women 9.21 years). We found that soybean products consumption is associated with the lower risk of gastric cancer among Koreans (the multivariate HRs for tofu consumption of more than two servings/week were 0.93 (95% CI: 0.68, 1.26; NS) among women and 0.63 (95% CI: 0.45, 0.89) among men). Among men with a body mass index of less than 25kg/m2, increased consumption of soybean paste (p for trend = 0.0188) and tofu (more than two servings/week vs. almost never consumed; HR 0.51 (0.32, 0.82) p for trend = 0.0095) was associated with decreased risk for gastric cancer.

Conclusion : Our results suggest that a high consumption of soybean products has a protective effect against gastric cancer

Citation Format: Woo-Kyoung Shin, Hwi-Won Lee, Dan Huang, Katherine De la Torre, Sukhong Min, Aesun Shin, Jong-koo Lee, Jung Eun Lee, Daehee Kang. Soybean products consumption decreases risk for gastric cancer: Results from the Health Examinees study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5911.
Abstract 6070: Functional natural killer cells derived from engineered hiPSC with hypoimmunity gene combo demonstrate hypoimmunity features in evading host attacks
Authors: Hu Jiabiao , He Xiangjun , Xu Jing , Zhou Yixuan , Yue Yanan , Gao Yangbin , Church George , Yang Luhan
Published: June 2022

Engineered human induced pluripotent stem cells (hiPSC)-derived allogeneic Natural Killer (NK) cells are emerging as promising safe and effective off-the-shelf cell therapy drugs. Repeated dosing of NK cells can partly compensate the relatively shorter persistence of NK cells compared with chimeric antigen receptor T cells (CAR-T); However, with each repeat, the persistence and efficacy are increasingly challenged by activation of host innate and adaptive immunity. Thus, reducing immunogenicity of allogeneic NK cells holds promise for better efficacy. In this study, we report a combination of “hypoimmunity” gene edits including multiple transgene knock-ins and both class I and class II MHC knockouts (2KO). We show that hiPSC engineered by the hypoimmunity combo can be efficiently differentiated into NK cells, comparable to the non-engineered ones. This is contrary to the notion from mouse studies that NK cells devoid of class I molecules are hypo-responsive, these engineered NK cells can be expanded by aAPC (artifitial Antigen Presenting Cells, a K562 cell line with surface expression of mbIL-21 and CD137L) and are capable of killing tumor cells, Additionally, we show that the engineered NK cells can evade T cell immunity, as examined by in vitro T cell proliferation and cytotoxicity assays. A humanized mouse model with transplanted CD34-positive human hematopoietic stem cells confirmed that the engineered NK cells can persist longer than WT and 2KO NK cells. Hypoimmune-QN-019 NK cells are generated by incorporating hypoimmunity gene combo edits into our hiPSC-derived NK cell clinical candidate QN-019 which has 3 transgenes including membrane-bound IL-15, high affinity non-cleavable CD16 and CAR targeting CD19. Comparing to QN-019, hypoimmune-QN-019 displayed better efficacy in humanized CDX mouse model in clearing CD19-positive cancer cells. Taken together, we have engineered hiPSC-derived allogeneic NK cells with hypoimmunity features, which hold great promise in becoming an off-the-shelf drug with improved in vivo persistence and efficacy for repeated dosing.

Citation Format: Jiabiao Hu, Xiangjun He, Jing Xu, Yixuan Zhou, Yanan Yue, Yangbin Gao, George Church, Luhan Yang. Functional natural killer cells derived from engineered hiPSC with hypoimmunity gene combo demonstrate hypoimmunity features in evading host attacks [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6070.
Abstract 6077: Mammalian adipose has many tumor features, which suggests the possible way of its evolutionary origin
Authors: Kozlov Andrei P.
Published: June 2022

Adipose expansion during obesity has remarkable similarities with the growth of solid tumors. These similarities are the following: the capability to unlimited expansion; reversible plasticity; induction of angiogenesis; chronic inflammation; remodeling and disfunction; systemic influence on the organism; hormone production; production of miRNAs that influence other tissues; immunosuppression; DNA damage and resistance to apoptosis; infiltration in other organs and tissues. The existing similarities between adipose and tumors suggest the possible evolutionary origin of mammalian adipose from some ancestral benign mesenchymal hereditary tumors.

Transgenic inducible zebrafish tumor model was used to verify the above hypothesis.

We described several genes, which originated in fish and were expressed in fish tumors. Their human orthologs LEP, SPRY1, PPARG, ID2, and CIDEA acquired functions connected with human adipose. They are also involved in tumor development in humans.

If the hypothesis of the evolutionary origin of mammalian adipose from the ancestral benign hereditary tumors is correct, it may open new opportunities to resolve the oncological problem and the problem of the obesity epidemic. New interventions targeting LEP, SPRY1, PPARG, ID2, and CIDEA gene network, in addition to what already is going on, can be designed for treatment and prevention of both obesity and tumors.

Citation Format: Andrei P. Kozlov. Mammalian adipose has many tumor features, which suggests the possible way of its evolutionary origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6077.
Abstract 6230: Loss of ALK4 function promotes cancer progression by regulating cell surface TGF-β receptor stability
Authors: Zhang Manqi , Chen Jian , Blobe Gerard Conrad
Published: June 2022

Pancreatic cancer is a lethal disease. More than 50% of pancreatic cancer patients are diagnosed with metastatic disease with a dismal 3% five-year survival rate. There is clearly an urgent need to identify novel targets to treat pancreatic cancer patients. Transforming growth factor-β (TGF-β) signaling is dysregulated during cancer progression, inhibiting tumorigenesis while promoting metastasis. Approximately half of pancreatic cancer patients have mutations of genes in the TGF-β signaling pathway, including SMAD4, SMAD3, TGFBR1, TFGBR2, ACVR1B, and ACVR2A. ALK4 (Activin receptor-like kinase 4), which is encoded by ACVR1B, is a type I receptor in the TGF-β superfamily. Mutation or copy number loss of ALK4 occurs in 34% of pancreatic cancer patients, while ALK4 expression is significantly down-regulated in many cancers, including pancreatic cancer, with low ALK4 expression associated with poor clinical outcomes. Here we demonstrate that loss of ALK4 increases cell migration and invasion, induces epithelial to mesenchymal transition (EMT), and promotes local and distal metastasis in pancreatic cancer models. Loss of ALK4 unexpectedly increases activation of the canonical TGF-β signaling pathway and significantly induces TGF-β-mediated expression of EMT mediators and effectors. Moreover, ALK4 loss increases the cell surface expression of TβRs (TGFβ receptor type I and II), without changing the receptor gene expression, by increasing N-linked glycosylation of TβRs, potentially by altering Golgi morphology and function. Proteomic analysis of newly synthesized proteins induced by ALK4 loss identified galectin-3 (Gal-3) as upregulated. Gal-3 is known to be upregulated by MGAT5 (Alpha-1,6-Mannosylglycoprotein 6-Beta-N-Acetylglucosaminyltransferase) and cross-links MGAT5-modified N-glycans on TβRs at the cell surface, suppressing TβRs endocytosis. Consistent with this observation, loss of ALK4 increased MGAT5 mRNA expression and induced Gal-3 protein expression, suggesting that ALK4 might regulate TβRs stability by promoting lattice formation with Gal-3 and preventing internalization. Taken together, our results suggest that the loss of ALK4 increases TβR receptor stability through regulating receptor glycosylation, activating TGF-β signaling, promoting the EMT transition and cancer progression.

Citation Format: Manqi Zhang, Jian Chen, Gerard Conrad Blobe. Loss of ALK4 function promotes cancer progression by regulating cell surface TGF-β receptor stability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6230.
Abstract 6247: Evaluation of AS-10, identified based on SAR studies of newly generated organoselenium compounds, as a potential colorectal cancer therapeutic acting potentially by acetylating histones
Authors: Johnson Hannah , Singh Amandeep , Raza Asif , Karelia Deepkamal , Plano Daniel , Amin Shantu , Sharma Arun
Published: June 2022

Colorectal cancer (CRC) is the third most common form of cancer diagnosed in the United States. Standard treatment for CRC utilizes a combination therapy composed of 5-fluorouracil, oxaliplatin, and folinic acid, known as FOLFOX. It has been established that patients with CRC tend to develop drug resistance to FOLFOX leading to a need for new chemotherapeutic treatments. Recent work has established that AS-10, a small molecule established for its promising role in treating pancreatic cancer, to be capable of inhibiting the growth of a range of CRC cell lines, including FOLFOX resistant CRC cells. Twenty-four cyclic and open chain analogs of AS-10 were synthesized and evaluated for their activity in inhibiting the viability of different cancer cells in vitro. The cell viability of these compounds was compared to AS-10 in the cell lines of pancreatic carcinoma (MiaPaCa2), lung carcinoma (H460), colorectal adenocarcinoma (HT29), colorectal carcinoma (HCT116), and FOLFOX resistant HT29 and HCT116 cells. Based on the IC50 values observed from these initial studies, only ASA-7, an open-chain alkyl selenocyanate, could treat all cancer cell lines in a similar concentration range of AS-10. Dose-response curves completed in 6 CRC cell lines indicated IC50 values in the range of 1-2 µM for AS-10 and 3.3-6.6µM for ASA-7. Cell viability evaluation in normal kidney (HEK293T) and colon (FHC) cell lines indicated AS-10 to be less toxic as compared to ASA-7. A similar trend was observed in vivo - AS-10 was 4 times more tolerable in mice as compared to ASA-7. A HCT116 xenograft study demonstrated the ability of AS-10 to significantly inhibit tumor growth in vivo without any apparent systemic toxicity. Moreover, AS-10 was assessed for its ability to act as an acetyl donor for histone acetyltransferase (HAT) and was found to initiate HAT activity in the absence of Acetyl-CoA in pancreatic epithelioid carcinoma (Panc-1) and colorectal carcinoma (HCT116) cells. In conclusion, AS-10 was identified as the best among the 24 analogs, in vitro and in vivo, when treating CRC and found to be capable of inducing HAT activity in both pancreatic and colorectal carcinoma elucidating a possible mechanism of action.

Citation Format: Hannah Johnson, Amandeep Singh, Asif Raza, Deepkamal Karelia, Daniel Plano, Shantu Amin, Arun Sharma. Evaluation of AS-10, identified based on SAR studies of newly generated organoselenium compounds, as a potential colorectal cancer therapeutic acting potentially by acetylating histones [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6247.
Abstract 6263: A pilot study to survey the exposure to secondhand smoke at home and at the workplace in Pakistan
Authors: Rehmat Shagufta , Khan Faisal F.
Published: June 2022

Globally over 7 million deaths are attributed to direct tobacco consumption whereas about 1.2 million people die due to the exposure to secondhand smoke (SHS). The health complications and mortalities caused by SHS exposure in Pakistan are also very prominent as it causes more than 33 thousand annual deaths. In this pilot study, we wanted to evaluate the exposure to secondhand smoke at work and at home, and its association with the prevalence of diseases through a survey based cross-sectional study. An online questionnaire was designed and developed using Google Forms and a short link was distributed using social media channels (i.e., WhatsApp groups and Facebook). Respondents were young adults from all cities of Pakistan who had access to internet and were digitally literate. Exposure to secondhand smoke at home, during childhood (from 0-18 year of age), adulthood exposure (after 18 years of age), and exposure at work was evaluated. The data was analyzed using Microsoft Excel and R.A total of 438 respondents participated in this survey with representation of male (54%) and female (46%) belonging to major cities in Pakistan, including Peshawar (38%), Islamabad (10.4%), Lahore (7.2%), and Karachi (6%). Overall, 75% of the study cohort were exposed to SHS, with the highest exposure noticed during adulthood with 70.3% of people being exposed to SHS after 18 years of age. Amongst those who were exposed daily at home, 63% had chronic bronchitis while 60% had cardiac diseases as self-reported health issues. Those exposed to SHS during childhood for 2 or more than 2 hours per week, 80% had self-reported chronic bronchitis in the survey. During adulthood, universities dominated as a location that offered highest exposure to SHS for 2 or more than 2 hours/week. One-year exposure history at workplace revealed that of those who were exposed to SHS at work ‘several times a day’, 60% had high blood pressure, 55% had asthma, while 50% had chronic bronchitis. At home ‘the father’ was identified as the main source of secondhand smoke and during adulthood universities are identified as place of highest exposure. At workplaces although the percentage of people exposed to secondhand smoke is lesser than those reported in previous studies but the correlation with medical complications was revealing. Overall throat irritation, gastric issues, and eye irritations were highly reported medical conditions amongst exposed individuals.

Citation Format: Shagufta Rehmat, Faisal F. Khan. A pilot study to survey the exposure to secondhand smoke at home and at the workplace in Pakistan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6263.
Abstract 733: Adolescent dietary patterns in relation to later prostate cancer risk and mortality in the NIH-AARP diet and health study
Authors: Lan Tuo , Park Yikyung , Colditz Graham A. , Liu Jingxia , Wang Molin , Wu Kana , Giovannucci Edward , Sutcliffe Siobhan
Published: June 2022

Background: Although adolescent diet has been proposed to contribute to prostate cancer (PCa) development, no studies have investigated the relation between adolescent dietary patterns and PCa risk or mortality.

Method: Using data from the NIH-AARP Diet and Health Study, we performed factor analysis to identify dietary patterns at ages 12-13 years. We further used Cox proportional hazards regression to examine hazard ratios (HRs) and 95% confidence intervals (CIs) of total, non-advanced, advanced, and fatal PCa.

Results: During 1,878,681 person-years of follow-up, 17,861 men were diagnosed with PCa, including 15,499 non-advanced, 2,362 advanced, and 832 fatal cancers. Three adolescent dietary patterns were identified: a Western modern pattern characterized by greater intake of sweets, processed meat, beef, cheese, and pizza; a plant-based pattern characterized by greater intake of vegetables, fruits, and dark bread; and a Western traditional pattern characterized by greater intake of gravy, bacon, and chicken, eggs, potatoes, green beans, legumes, and white bread. Although not entirely consistent across analyses, a higher adolescent plant-based pattern score was associated with reduced risks of total PCa (fully-adjusted HRQ5vs.Q1=0.93, 95% CI: 0.89-0.98, p-trend=0.003) and non-advanced PCa (HR=0.91, 95% CI: 0.87-0.96, p-trend<0.001), whereas no associations were observed for Western modern or Western traditional patterns.

Conclusions: In the first study, to our knowledge, to investigate adolescent dietary patterns and PCa risk, we found some evidence to support a protective role for a plant-based diet during adolescence on PCa risk. Our findings may inform the development of new, primary prevention strategies for PCa.

Citation Format: Tuo Lan, Yikyung Park, Graham A. Colditz, Jingxia Liu, Molin Wang, Kana Wu, Edward Giovannucci, Siobhan Sutcliffe. Adolescent dietary patterns in relation to later prostate cancer risk and mortality in the NIH-AARP diet and health study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 733.
Abstract LB056: The spatial landscape of progression and immunoediting in primary melanoma at single cell resolution
Authors: Nirmal Ajit Johnson , Maliga Zoltan , Vallius Tuulia , Quattrochi Brian , Chen Alyce , Jacobson Connor , Pelletier Roxanne , Yapp Clarence , Arias-Camison Raquel , Chen Yu-An , Lian Christine , Murphy George F. , Santagata Sandro , Sorger Peter K.
Published: June 2022

Cutaneous melanoma is a highly immunogenic malignancy, surgically curable at early stages, but life-threatening when metastatic. The spatial organization of the tumor ecosystem during early-stage melanoma is not well understood. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially-resolved micro-region transcriptomics to study immune evasion and immunoediting in primary melanoma. We collected highly multiplexed single-cell data from 70 distinct histological regions from 13 specimens (patients) selected to have multiple progression-associated histologies within a single resection. These histologies range from pre-malignant fields in which melanocytic atypia represents the first steps in cancer initiation to non-invasive (radial growth phase) and invasive (vertical growth phase) primary melanoma that eventually gives rise to disseminated disease. We find that recurrent cellular neighborhoods involving tumor, immune, and stromal cells change significantly along a progression axis involving precursor states, melanoma in situ, and primary invasive tumor. Hallmarks of immunosuppression were detectable as early as the melanoma precursor stage, and when tumors become locally invasive, a consolidated and spatially restricted environment with multiple overlapping immunosuppressive mechanisms forms along the tumor-stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1 and by PDL1-expressing macrophages and dendritic cells engaging activated T cells. However, only a few millimeters away, T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can co-exist within a few millimeters of each other in a single specimen. Multiplexed single-cell imaging and micro-region mRNA profiling link morphological and molecular features of tumor evolution within and across primary cancer specimens, revealing highly localized programs of immune and tumor cell communication via paracrine cytokine signaling and direct cell-cell contact.

Citation Format: Ajit Johnson Nirmal, Zoltan Maliga, Tuulia Vallius, Brian Quattrochi, Alyce Chen, Connor Jacobson, Roxanne Pelletier, Clarence Yapp, Raquel Arias-Camison, Yu-An Chen, Christine Lian, George F. Murphy, Sandro Santagata, Peter K. Sorger. The spatial landscape of progression and immunoediting in primary melanoma at single cell resolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB056.
Abstract LB126: Functional limitations in respiratory complex I underlie mitochondrial bioenergetics in human colorectal adenocarcinoma
Authors: Boykov Ilya , Montgomery McLane M. , Hagen James T. , Coalson Hannah S. , Fisher-Wellman Kelsey H.
Published: June 2022

Typified by oxidative phosphorylation (OXPHOS), mitochondria catalyze a wide variety of cellular processes now understood to be critical for malignant growth. As such, there is considerable interest in targeting mitochondrial OXPHOS in cancer. The present project was based on the premise that the development of efficacious mitochondrial-targeted anti-cancer compounds requires answering two fundamental questions: 1) is mitochondrial bioenergetics in fact different between cancer and non-cancer cells? and 2) If so, what are the underlying mechanisms? To address these questions, we developed a methodological workflow designed to integrate in vitro functional readouts of mitochondrial flux with mass-spectrometry-based proteomics. This allowed us to directly quantitate both total respiratory capacity and OXPHOS kinetics on a per mitochondrion basis. Experiments were performed in isolated mitochondria prepared from freshly resected human colorectal adenocarcinomas (COAD). Relative to adjacent normal colonic mucosa, tumor mitochondria consistently presented with partial disruptions in respiratory complex I (CI). Surprisingly, CI functional limitations did not impair absolute oxidative flux. Instead, the tumor mitochondrial network displayed clear evidence of intrinsic remodeling. Such remodeling maintained respiratory competence at the expense of decreased oxidative ATP synthesis (i.e., OXPHOS inefficiency or increased ‘uncoupling’). Given recent findings demonstrating that mitochondrial OXPHOS is dispensable for tumor growth, our data raise the intriguing possibility that the requirement for mitochondria in COAD may have little to do with oxidative ATP production, but instead reflect a requirement for accelerated mitochondrial flux to support other aspects of anabolic growth (e.g., extracellular nutrient uptake, NAD+ regeneration, nucleotide synthesis). In this respect, rather than functioning as energy producers, COAD mitochondria may primarily function as ‘energy sinks’.

Citation Format: Ilya Boykov, McLane M. Montgomery, James T. Hagen, Hannah S. Coalson, Kelsey H. Fisher-Wellman. Functional limitations in respiratory complex I underlie mitochondrial bioenergetics in human colorectal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB126.
Abstract LB198: Cellular selectivity of STING stimulation determines priming of anti-tumor T cell responses
Authors: Jneid Bakhos , Bochnakian Aurore , Delisle Fabien , Djacoto Emeline , Denizeau Jordan , Sedlik Christine , Fiore Frédéric , Kramer Robert , Walters Ian , Carlioz Sylvain , Malissen Bernard , Piaggio Eliane , Manel Nicolas
Published: June 2022

T cells that recognize tumor antigens are crucial for anti-tumor immune responses. Induction of anti-tumor T cells in immunogenic tumors depends on STING, the intracellular innate immune receptor for cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) and related cyclic dinucleotides (CDN). However, the optimal way to leverage STING activation in non-immunogenic tumors is still unclear. Here, we show that cGAMP delivery by intra-tumoral injection of virus-like particles (cGAMP-VLP) leads to differentiation of tumor-specific T cells, decrease in tumor regulatory T cells (Tregs) and anti-tumoral responses that synergize with PD1 blockade. By contrast, intra-tumoral injection of synthetic CDN leads to tumor necrosis and systemic T cell activation but no differentiation of tumor-specific T cells, and a demise of immune cells in injected tumors. Analyses of cytokine responses and genetic models revealed that cGAMP-VLP preferentially targets STING in dendritic cells at a 1000-fold less dose than synthetic CDN. Sub-cutaneous administration of cGAMP-VLP showed synergy when combined with a tumor Treg-depleting antibody to elicit systemic tumor-specific T cells, leading to complete and lasting tumor eradication. These findings show that cell targeting of STING stimulation shapes the anti-tumor T cell response and reveal a therapeutic strategy with T cell modulators, which may address the current limitations of STING-based approaches in patients.

Citation Format: Bakhos Jneid, Aurore Bochnakian, Fabien Delisle, Emeline Djacoto, Jordan Denizeau, Christine Sedlik, Frédéric Fiore, Robert Kramer, Ian Walters, Sylvain Carlioz, Bernard Malissen, Eliane Piaggio, Nicolas Manel. Cellular selectivity of STING stimulation determines priming of anti-tumor T cell responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB198.
Abstract LB206: Characterizing the PK/PD relationship of C/EBPβ antagonist peptide ST101 in a mouse orthotopic breast cancer model
Authors: Rotolo Jim , Koester Mark , Ramirez Rick , Gallagher Erin , Ghamsari Lila , Leong Siok , Darvishi Emad , Gonzales Jerel , Taylor Timothy , Upton Richard , Merutka Gene , Kappel Barry
Published: June 2022

The transcription factor CCAAT/Enhancer Binding Protein β (C/EBPβ) is aberrantly activated in many cancers, where it drives a genetic profile that promotes survival and proliferation of tumor cells and inhibits differentiation. ST101 is a peptide antagonist of C/EBPβ that prevents its dimerization by binding the leucine zipper domain, ultimately targeting C/EBPβ for proteosomal degradation. Here we describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of ST101 in a non-clinical orthotopic breast cancer model. An integrated population PK/PD model was developed to describe the exposure−response relationship for ST101 anti-tumor activity in female Balb/c mice bearing 4T1-luc triple-negative breast cancer orthotopic tumors. Exposure−response predictions were made based on estimated potency in mice and mean plasma concentrations observed at the doses investigated. Approximately 100% tumor growth inhibition (TGI) was observed at the highest doses administered in this study. The AUC values required to achieve IC50 and IC90 were 80,500 and 99,600 ng/ml*hr, respectively, corresponding to cumulative doses of 97 mg/kg and 120 mg/kg per week in mice. The integrated model provides a useful tool to characterize and predict the ST101 dose-response relationship, provide a quantitative rationale for dose selection in a phase 2 clinical trial and supports the continued development of ST101 as a potent peptide therapeutic for patients with solid tumors.

Citation Format: Jim Rotolo, Mark Koester, Rick Ramirez, Erin Gallagher, Lila Ghamsari, Siok Leong, Emad Darvishi, Jerel Gonzales, Timothy Taylor, Richard Upton, Gene Merutka, Barry Kappel. Characterizing the PK/PD relationship of C/EBPβ antagonist peptide ST101 in a mouse orthotopic breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB206.
Geometria Olímpica com Geogebra - v. 3
Authors:   Universidade de São Paulo. Faculdade de Zootecnia e Engenharia de Alimentos, Linares Juan López , Santos João Paulo Martins dos ,   Academia da Força Aérea em Pirassununga/SP, Jesus Alessandro Firmiano de ,   Academia da Força Aérea em Pirassununga/SP
Published: June 2022

Este material didático foi utilizado durante algumas das aulas do curso "Geometria Olímpica com GeoGebra" para professores de Matemática do Ensino Fundamental e Médio de todo o Brasil. O livro conta com 57 figuras que facilitam acompanhar a resolução das questões propostas. A discussão é organizada em quatro capítulos: Desigualdade de Ptolomeu; Teorema de Casey; Cálculos de Áreas; e Teoremas de Menelaus, Pascal e Ceva. O diferencial na utilização do GeoGebra está baseado na disponibilidade gratuita do software, tanto online como em aplicativos para computadores e celulares. As construções geométricas podem ser realizadas de forma dinâmica, em que são exploradas diversas configurações de um mesmo problema. O GeoGebra serve tanto como calculadora gráfica e numérica, utilizada para a verificação, como ferramenta para a apresentação, passo a passo, de uma demonstração rigorosa.
Ressoar digital: estudo de caso sobre os canais digitais do NEOJIBA
Authors: Gonçalves Hugo Leonardo Nascimento , Marback Heitor Ferrari
Published: June 2022

O presente artigo investiga, mediante estudo de caso, o impacto do consumo de conteúdos divulgados pelos Núcleos Estaduais de Orquestras Juvenis e Infantis da Bahia (NEOJIBA) em suas redes sociais, na pandemia. Logo, constatou-se a hipótese de que, no cenário em questão, a utilização frequente das plataformas digitais vem assegurando ao público uma forma inédita de fruição dessas publicações. Visando a elucidar tal teoria, foram analisados o engajamento e o alcance das postagens publicadas em maio de 2021 nos canais do NEOJIBA no Instagram e no YouTube. Além disso, este trabalho evidencia um panorama sucinto das orquestras, bem como estabelecer um paralelo entre elas e sua presença hoje recorrente nos meios digitais. A conclusão é que os entusiastas de música erudita vêm consumindo em potencial os conteúdos hospedados nas redes do programa.
Perspectivas pretas que enunciam vozes e educam: o feminismo Hip-Hop, a política da sobrevivência e o empoderamento na favela
Authors: Dias Cristiane Correia
Published: June 2022

Frente às dificuldades encontradas no sistema educacional vigente, lançaremos sementes para um novo porvir, ressaltando as potencialidades de uma educação viva, entre vida, arte e conhecimento, presente na favela, enquanto corpo-território que tem sido reconfigurado pelo movimento de jovens mulheres e suas novas linguagens. O Hip-Hop (EUA), o Funk (Brasil) e o Slam (EUA) são movimentos socioculturais, políticos e educacionais que têm contribuído para o movimento refavela. A ideia é decodificar a gramática desses movimentos, propondo uma leitura desses novos tempos a fim de contribuir com um novo léxico (Cf. SILVA, 2018), a ser tracejado a partir da luta de mulheres negras face à opressão histórica e sexual que se transmutam por meio da arte, para analisarmos em que medida a busca emancipada da voz, com suas dinâmicas e nuances, subverte os modus operandi vigentes, que estão imbricados na intersecção entre a política da sobrevivência, a autodefinição e a política do empoderamento.
Vida favorecida colorida: vou te contar, a vida na favela não é fácil não!
Authors: Amaral Mônica , Dias Marina Nunes , Santos Robson Guarnieri dos
Published: June 2022

Com base em nossas experiências de docência compartilhada em sala de aula com professores e estudantes do 7º ano em uma escola municipal, destacamos as afinidades entre as narrativas de videoclipes de rappers do próprio território das comunidades do entorno e as vivências dos jovens, de maneira a potencializar reflexões críticas e uma escrita sensível às mazelas que os atingem como sujeitos. Ao propor videoclipes, como “De onde eu venho” (Edi Rock e Mc Pedrinho, 2019), testemunhamos o despertar de uma memória afrodiaspórica e a escrita de raps pelos próprios estudantes sobre o significado de suas origens, como estratégia de denúncia e de combate às desigualdades raciais e de classe. Propomos uma leitura desta experiência dos pontos de vista, estético (BENJAMIN, 1980; ADORNO, 1986), do território (SANTOS, 1998, 2009) e de uma narrativa engajada, presente na literatura (JESUS, 2020; HOOKS, 2017) e na poesia do rap.
Doações da Colección Patricia Phelps de Cisneros: estratégias na internacionalização de obras de arte latino-americanas.
Authors: Crubelatti Vitor
Published: June 2022

O presente artigo busca sistematizar por meio de consultas a bancos de dados de museus e jornais, além de informações do próprio site da Colección Patricia Phelps de Cisneros (CPPC), uma das principais estratégias de internacionalização de obras de arte latino-americanas utilizadas pela CPPC: doações a museus norte-americanos e europeus. De forma mais específica, este estudo procura entender as dinâmicas e impactos dessas doações tendo como base uma grande doação realizada pela CPPC em 2018 (202 obras latinas de arte contemporânea) para seis museus ao redor do mundo: Museum of Modern Art (MoMA), Museo Nacional Centro de Arte Reina Sofía, Museo de Arte Moderno Buenos Aires, Museo de Arte de Lima (MALI), Bronx Museum of the Arts e Blanton Museum of Art at the University of Texas.
Necropolítica bolsonarista e discurso autoritário: considerações acerca dos impactos causados às pessoas que vivem com HIV
Authors: Santos Everton da Silva
Published: June 2022

A proposta deste artigo é, assertivamente, investigar em que modo as ações necropolíticas instituídas ao longo dos dois primeiros anos de governo Bolsonaro permitiram a continuidade da estigmatização e estereotipação das pessoas que vivem com HIV (PVHIV) no Brasil. Propusemos analisar discursos autoritários proferidos pelo presidente da República em 2020, que incute na perpetuação do estigma, na violência da sociedade e negligência do Estado, bem como a violação dos Direitos Humanos, tendo como resultado a marginalização e invisibilidade destes sujeitos. Sob a perspectiva qualitativa dos estudos sociais, considerar-se-á as reflexões suscitadas por Mbembe (2017) para analisar as formas de controle enquanto mecanismo de poder; e por Adorno (1995), para verificar como o discurso excludente de Bolsonaro ameaça esse grupo social.
Os estudos de recepção latino-americanos como potência contra-hegemônica no campo da comunicação: a perspectiva das mediações
Authors: Ortiz Felipe Chibás , Dainezi Gustavo Fernandes , Dias Ana Paula
Published: June 2022

O presente artigo procura discutir, de um lado, o desenvolvimento dos estudos de recepção latinoamericanos como potência epistemológica contra-hegemônica que oferece ao campo da comunicação uma perspectiva emancipatória e um cabedal teórico-metodológico capazes de reorientar a pesquisa na região e, de outro, a consolidação ao longo das quatro décadas desses estudos, da perspectiva das mediações de Jesús Martín-Barbero, a partir de seus quatro mapas das mediações e sua cartografia. As metodologias utilizadas são a revisão bibliográfica e a análise hermenêutica. Como resultado, esperamos apresentar perspectivas de investigação barberiana sobre a comunicação contemporânea e apontar de que maneiras sua cartografia e seus mapas contribuem para a constante emancipação decolonial da américa latina.
Quilombos, a memória e os saberes da resistência negra
Authors: Silva Thais Pereira da
Published: June 2022

Os quilombos guardam, transmitem e atualizam as memórias e os saberes africanos e afro-brasileiros. De acordo com dados da Fundação Cultural Palmares, existem mais de seis mil comunidades remanescentes quilombolas. O objetivo desta pesquisa é refletir sobre as memórias e os saberes corporais e orais dos quilombolas. Para isso, o estudo é revisão bibliográfica. Além disso, mobiliza-se documentários realizado sobre o Jongo do Sudeste e o Sistema Agrícola Tradicional Quilombola do Vale do Ribeira, para analisar os agentes.
Editais de emergência cultural na Bahia: gestores públicos e manutenção do existente
Authors: Silveira Isabela Fernanda Azevedo , Coelho Amanda Haubert Ferreira
Published: June 2022

Este texto analisa os editais de emergência cultural implementados no Estado da Bahia por ocasião da crise sanitária causada pelo COVID-19, que levou ao cancelamento amplo e duradouro de atividades de diferentes naturezas, motivando a liberação de recursos federais por meio da Lei 14.017/2020, conhecida como Lei Aldir Blanc, para suporte ao setor cultural. Analisamos comparativamente as chamadas destinadas às linguagens artísticas e à preservação de bens e expressões populares, engajando teorias de Eagleton (2003), Vich (2014; 2017), Bourdieu (2004) e Nussbaumer (2020), dentre outros, para problematizar a condução da instituição promotora do edital, a Secretaria de Cultura do Estado da Bahia (SecultBA), na manutenção ou confrontamento de aspectos de exclusão de determinadas comunidades de direitos.