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This is the second of three papers dealing with metal-bearing circumneutral mine drainage from the inactive Rico-Argentine mine site located at an elevation of ≈ 2740 m (9000 feet) in the San Juan mountain range in southwestern Colorado. This paper evaluates two years of mine drainage treatment using a passive system that included a vertical-flow engineered biotreatment cell. The collapsed St. Louis Tunnel (SLT) discharges circumneutral mine water from several sources that contains elevated concentrations of Cd, Cu, Fe, Mn, Zn. A demonstration-scale 114 L/min (30 gpm) gravity-flow passive treatment system was installed, consisting of a settling basin (utilizing coagulant addition to improve suspended solids settling efficiency), an anaerobic sulfate-reducing bioreactor, and an aeration cascade for effluent polishing. The treatment system generally met target treatment goals for Cd, Cu, Fe, and Pb. Nanophase ZnS in system effluent decreased the frequency of meeting total Zn project treatment goals. Unexpectedly high levels of Mn removal were observed in both the anaerobic bioreactor and the aeration cascade. Large seasonal variations in influent metals concentrations and pH present the greatest challenge in managing system performance.

Myopia prevention and anti-myopia treatment is of great importance in South East Asia.To evaluate the prevalence and related factors of myopic retinopathy in Vietnam.A cross-sectional study was conducted on 168 eyes of 88 patients with high myopia presenting to the Refraction Department of Vietnam National Eye Hospital. Inclusion criteria were high myopia (≤-6.00D with cycloplegic retinoscopy). Consecutive presenting patients recruited between January 2020 and August 2020 consented to participate.Participant age range was 12-47 years. Peripapillary atrophy was present in 70.2% of participants, most commonly atrophy of one-quarter of the disc (38.7%). Central retinal changes were present in 66.1% of participants, subclassified as tessellated fundus in 60.7%, diffuse chorioretinal atrophy in 4.2% and patchy chorioretinal atrophy in 1.2%. Peripheral retinal lesions were present in 43.5% of participants, consisting of white-without-pressure in 32.1%, lattice degeneration in 16.1%, snail track degeneration in 4.2% and microcystoid degeneration in 1.2%. Myopia ≤-8.00D and axial length ≥26.5 mm were associated with additional risk of posterior ocular complications. Furthermore, age ≥19 years increased risk of central myopic retinopathy and ≥10 years since initial myopia diagnosis increased the risk of peripapillary atrophy and central retinal changes. Other factors such as the age of onset of myopia and family myopia history did not appear to alter the risk of peripheral retina damage.Retinal disorders were common in Vietnamese people with high myopia. Within the current cohort with high myopia, myopia ≤-8.00D and axial length ≥26.5 mm were associated with a significant further elevation of risk.

In 2021, WHO Member States endorsed a global target of a 40-percentage-point increase in effective refractive error coverage (eREC; with a 6/12 visual acuity threshold) by 2030. This study models global and regional estimates of eREC as a baseline for the WHO initiative.The Vision Loss Expert Group analysed data from 565 448 participants of 169 population-based eye surveys conducted since 2000 to calculate eREC (met need/[met need + undermet need + unmet need]). A binary logistic regression model was used to estimate eREC by Global Burden of Disease (GBD) Study super region among adults aged 50 years and older.In 2021, distance eREC was 79·1% (95% CI 72·4-85·0) in the high-income super region; 62·1% (54·7-68·8) in north Africa and Middle East; 49·5% (45·0-54·0) in central Europe, eastern Europe, and central Asia; 40·0% (31·7-48·2) in southeast Asia, east Asia, and Oceania; 34·5% (29·4-40·0) in Latin America and the Caribbean; 9·0% (6·5-12·0) in south Asia; and 5·7% (3·1-9·0) in sub-Saharan Africa. eREC was higher in men and reduced with increasing age. Global distance eREC increased from 2000 to 2021 by 19·0%. Global near vision eREC for 2021 was 20·5% (95% CI 17·8-24·4).Over the past 20 years, distance eREC has increased in each super region yet the WHO target will require substantial improvements in quantity and quality of refractive services in particular for near vision impairment.WHO, Sightsavers, The Fred Hollows Foundation, Fondation Thea, Brien Holden Vision Institute, Lions Clubs International Foundation.

Health education interventions are more commonly evaluated in hospitals or schools but rarely in the community. The purpose of this study was to assess the effects of a community-based eye health e...

Wnt-Fzd signalling pathway plays a critical role in acute myeloid leukaemia (AML) progression and oncogenicity. There is no study to investigate the prognostic value of Wnt and Fzd gene families in AML. Our study screened 84 AML patients receiving chemotherapy only and 71 also undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) from the Cancer Genome Atlas (TCGA) database. We found that some Wnt and Fzd genes had significant positive correlations. The expression levels of Fzd gene family were independent of survival in AML patients. In the chemotherapy group, AML patients with high Wnt2B or Wnt11 expression had significantly shorter event-free survival (EFS) and overall survival (OS); high Wnt10A expressers had significantly longer OS than the low expressers (all P < .05), whereas, in the allo-HSCT group, the expression levels of Wnt gene family were independent of survival. We further found that high expression of Wnt10A and Wnt11 had independent prognostic value, and the patients with high Wnt10A and low Wnt11 expression had the longest EFS and OS in the chemotherapy group. Pathway enrichment analysis showed that genes related to Wnt10A, Wnt11 and Wnt 2B were mainly enriched in 'cell morphogenesis involved in differentiation', 'haematopoietic cell lineage', 'platelet activation, signalling and aggregation' and 'mitochondrial RNA metabolic process' signalling pathways. Our results indicate that high Wnt2B and Wnt11 expression predict poor prognosis, and high Wnt10A expression predicts favourable prognosis in AML, but their prognostic effects could be neutralized by allo-HSCT. Combined Wnt10A and Wnt11 may be a novel prognostic marker in AML.

The Victorian Aboriginal Spectacles Subsidy Scheme (VASSS) aimed to improve access to visual aids and eye care for Aboriginal and Torres Strait Islander Victorians. The VASSS started in July 2010 and has operated continually since. In 2016, we explored the collaborations, planning, adaptations and performance of the VASSS over the first 6 years by reviewing and analysing service data, as well as data from semistructured interviews, focus groups and surveys. An estimated 10 853 VASSS cofunded visual aids were delivered over 6 years, and the mean annual number of comprehensive eye examinations provided within services using VASSS grew 4.6-fold faster compared with the 4 years preceding the VASSS. We estimate that 16% and 19% of recipients presented with distance and near vision impairments respectively, all of which were corrected with visual aids. VASSS achievements were attained through collaborations, flexibility, trust and communication between organisations, all facilitated by funding resulting from evidence-based advocacy. Access to visual aids and eye examinations by Aboriginal Victorians has improved during the operation of the VASSS, with associated direct and indirect benefits to Aboriginal health, productivity and quality of life. The success of the VASSS may be replicable in other jurisdictions and provides lessons that may be applicable in other fields. What is known about the topic? The 2009 National Indigenous Eye Health Survey estimated that the age-adjusted prevalence of vision impairment was 2.8-fold higher and the prevalence of blindness 6.2-fold higher among adult Aboriginal Australians compared with non-Aboriginal Australians, predominantly due to uncorrected refractive error and cataract. What does this paper add? Implemented in 2010, the Victorian Aboriginal Spectacles Subsidy Scheme (VASSS) has been supported, designed and well received by stakeholders and, critically, the Aboriginal community. The VASSS has successfully improved access to comprehensive eye examinations and high-quality affordable visual aids (principally spectacles, with cost certainty). What are the implications for practitioners? The VASSS demonstrates the power of collaborative partnerships and the potential for solutions targeted at specific components of a system to generate wider benefits, including the reduction of the prevalence and burden of vision impairment by correcting refractive error, managing vision-threatening eye disease and increasing awareness of eye health issues.

The German version of the Highly Sensitive Person Scale (HSPS-G) is an instrument for the assessment of sensitivity. Validity of the scale was confirmed in prior research (KonradHerzberg, 2017). This paper provides norm values of the HSPS-G for German-speaking countries.To generate norms, data from 7458 participants (6251 female, 1207 male; age ranging: 14-80 years; mean=37.80; SD=11.75) were collected in an online assessment. Participants were German-speaking citizens of Germany, Austria, and Switzerland.Analysis of variance suggested systematic gender differences in the scores. Thus, gender-specific norms were created for the subscales and the total score of the HSPS-G. The resulting norm values comprising percentiles and T-values enable comparative interpretation of the results of the HSPS-G, enabling the assessment of inter- and intraindividual differences with respect to demographic variables.Die deutsche Fassung der Highly Sensitive Person Scale (HSPS-G) ist ein Verfahren zur Feststellung der Ausprägung des Merkmals Feinfühligkeit. Diese Skala wurde bisher in der deutschen Fassung validiert (KonradHerzberg, 2017), eine Normierung für die deutschsprachige Allgemeinbevölkerung steht allerdings noch aus.Zur Erstellung von Normwerten der Skala für die Allgemeinbevölkerung wurden N=7458 Personen (n=6251 Frauen, n=1207 Männer) im Alter von 14–80 Jahren (MW=37.80, SD=11.75) im deutschsprachigen Raum (Deutschland, Österreich, Schweiz) online befragt.Die Varianzanalyse zeigte höhere Werte für Frauen, so dass geschlechtsspezifische Normen notwendig sind. Daher werden geschlechtsspezifische Normwerte für die Subskalen der HSPS-G als auch für den HSPS-G-Gesamtscore bereitgestellt. Mit diesen Prozenträngen und T-Werten stehen erstmals Vergleichsdaten für das im deutschen Sprachraum etablierte Instrument zur Verfügung, die die Interpretation interindividueller und intraindividueller Unterschiede vor dem Hintergrund von Bevölkerungsangaben erlauben.

Purpose We estimated the potential global economic productivity loss resulting from vision impairment (VI) and blindness as a result of uncorrected myopia and myopic macular degeneration (MMD) in 2015. Clinical Relevance Understanding the economic burden of VI associated with myopia is critical to addressing myopia as an increasingly prevalent public health problem. Methods We estimated the number of people with myopia and MMD corresponding to critical visual acuity thresholds. Spectacle correction coverage was analyzed against country-level variables from the year of data collection; variation in spectacle correction was described best by a model based on a human development index, with adjustments for urbanization and age. Spectacle correction and myopia data were combined to estimate the number of people with each level of VI resulting from uncorrected myopia. We then applied disability weights, labor force participation rates, employment rates, and gross domestic product per capita to estimate the potential productivity lost among individuals with each level and type of VI resulting from myopia in 2015 in United States dollars (US$). An estimate of care-associated productivity loss also was included. Results People with myopia are less likely to have adequate optical correction if they are older and live in a rural area of a less developed country. The global potential productivity loss associated with the burden of VI in 2015 was estimated at US$244 billion (95% confidence interval [CI], US$49 billion–US$697 billion) from uncorrected myopia and US$6 billion (95% CI, US$2 billion—US$17 billion) from MMD. Our estimates suggest that the Southeast Asia, South Asia, and East Asia Global Burden of Disease regions bear the greatest potential burden as a proportion of their economic activity, whereas East Asia bears the greatest potential burden in absolute terms. Conclusions Even under conservative assumptions, the potential productivity loss associated with VI and blindness resulting from uncorrected myopia is substantially greater than the cost of correcting myopia.

The global burden of myopia is growing. Myopia affected nearly 30% of the world population in 2020 and this number is expected to rise to 50% by 2050. This review aims to analyze the impact of myopia on individuals and society; summarizing the evidence for recent research on the prevalence of myopia and high myopia, lifetime pathological manifestations of myopia, direct health expenditure, and indirect costs such as lost productivity and reduced quality of life (QOL). The principal trends are a rising prevalence of myopia and high myopia, with a disproportionately greater increase in the prevalence of high myopia. This forecasts a future increase in vision loss due to uncorrected myopia as well as high myopia-related complications such as myopic macular degeneration. QOL is affected for those with uncorrected myopia, high myopia, or complications of high myopia. Overall the current global cost estimates related to direct health expenditure and lost productivity are in the billions. Health expenditure is greater in adults, reflecting the added costs due to myopia-related complications. Unless the current trajectory for the rising prevalence of myopia and high myopia change, the costs will continue to grow. The past few decades have seen the emergence of several novel approaches to prevent and slow myopia. Further work is needed to understand the life-long impact of myopia on an individual and the cost-effectiveness of the various novel approaches in reducing the burden.

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, is constitutively activated in various human cancers, and has been recognized as an attractive therapeutic target in cancer. STAT3 protein dimerizes and translocates to the nucleus to eventually transactivate downstream target genes. Despite some progress has been made in the past two decades, to date there is still lack of FDA-approved STAT3 inhibitors available for clinical use. Recently, proteolysis-targeting chimera (PROTAC) technology has dramatically advanced the development of therapeutics by introducing targeted protein degradation. Previously, our team has developed HJC0152, a promising STAT3 inhibitor, via structure- and fragment-based drug design strategies and in silico molecular modeling and docking. HJC0152 has demonstrated an attractive cancer therapeutic and preventive efficacy by targeting the non- estrogen receptor (ER)-based STAT3 signaling pathway. To achieve better potency and inhibition of STAT3 signaling, we therefore developed a series of HJC0152-based PROTAC protein degraders. These potential anticancer agents have been initially evaluated and several showed favorable potency in inhibiting the proliferation in a panel of breast cancer cell lines. We found that compounds JMX1122, JMX1123, and JMX1124 significantly inhibited proliferation and colony formation of a highly aggressive triple-negative breast cancer (TNBC) cell line, MDA-MB-231, and the ER-positive breast cancer cell lines. Different from the lead compound HJC0152, which showed an early inhibition on the phosphorylation of STAT3 at the Tyr705 and Ser727 residues, the newly developed HJC0152-PROTACs showed a significantly late differential inhibition of STAT3 phosphorylation at the Tyr705 and Ser727 residues, and reduced the total STAT3 protein level at 72 hours of treatment. Our current results support the notion that HJC0152-based PROTAC degraders potently suppress breast cancer cell proliferation and induce apoptosis, via direct targeting of STAT3 and its protein degradation. These compounds are currently being investigated for breast cancer cell migration and invasion, and will be evaluated for the in vivo inhibition of tumor growth and metastasis in different mouse models. This project is supported by NIH/NCI Awards R01CA226001 and R01CA231150 to Q.S. and J.Z. Citation Format: Junhai Xu, Jimin Xu, Ruixia Ma, Mingxiang Zhou, Doerte R. Fricke, Haiying Chen, Hyejin Kim, Xi Liu, Jia Zhou, Qiang Shen. Development of HJC0152-based proteolysis-targeting chimera degraders for breast cancer 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 424.

Natural products provide a wealth of resources as the molecular starting point for the development of therapeutic agents, including a plethora of anticancer drugs currently in clinical use. Oridonin is a natural diterpene compound enriched in the medicinal herb Rabdosia rubescens, and its anticancer property has been extensively studied. However, the potency of oridonin against triple-negative breast cancer (TNBC) limits its potential clinical translation. Previously, we developed a class of oridonin analogues including CYD0618 and others as effective anticancer agents to inhibit tumor growth of TNBC in vitro and in vivo. Intriguingly, CYD0618 has been shown to directly bind to and inhibit STAT3 transcription factor, which is constitutively activated in the majority of human cancers. Currently there are no FDA-approved direct STAT3 inhibitors in clinical use. Based on the proteolysis-targeting chimera (PROTAC) technology, our team designed novel oridonin- and CYD0618-based PROTACs in an attempt to achieve specific STAT3 binding and protein degradation. We determined anticancer effects of oridonin- and CYD0618-PROTACs on proliferation, colony formation, and apoptosis of the TNBC cell line MDA-MB-231. We found that oridonin- and CYD0618-based PROTACs inhibited the proliferation of MDA-MB-231 cells significantly, similarly effective as the lead compound CYD0618 and much more potent than oridonin. We then examined the expression of STAT3, pSTAT3 and protein biomarkers for tumor metastasis using Western blot. STAT3 and pSTAT3 protein levels were downregulated dose- and time-dependently in MDA-MB-231 cells treated with CYD0618 and CYD0618-PROTACs, respectively. Our results demonstrate impressive effects of CYD0618-based PROTACs against TNBC cells, primarily through direct targeting of STAT3. We are in the process of further characterizing the molecular profile of CYD0618-based PROTACs by studying its interaction with STAT3 and protein degradation as well as their efficacy against TNBC tumor xenografts in vivo. Citation Format: Ruixia Ma, Pingyuan Wang, Junhai Xu, Jimin Xu, Doerte R. Fricke, Yu Xue, Hyejin Kim, Haiying Chen, Xi Liu, Jia Zhou, Qiang Shen. Development of oridonin-based proteolysis-targeting chimera (PROTAC) degraders as effective breast cancer therapeutics [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 426.

Supplemental digital content is available in the text., SIGNIFICANCE Quality refractive error care is essential for reducing vision impairment. Quality indicators and standardized approaches for assessing the quality of refractive error care need to be established. PURPOSE This study aimed to develop a set of indicators for assessing the quality of refractive error care and test their applicability in a real-world setting using unannounced standardized patients (USPs). METHODS Patient outcomes and three quality of refractive error care (Q.REC) indicators (1, optimally prescribed spectacles; 2, adequately prescribed spectacles; 3, vector dioptric distance) were developed using existing literature, refraction training standards, and consulting educators. Twenty-one USPs with various refractive errors were trained to visit optical stores across Vietnam to have a refraction, observe techniques, and order spectacles. Spectacles were assessed against each Q.REC indicator and tested for associations with vision and comfort. RESULTS Overall, 44.1% (184/417) of spectacles provided good vision and comfort. Of the spectacles that met Q.REC indicators 1 and 2, 62.5 and 54.9%, respectively, provided both good vision and comfort. Optimally prescribed spectacles (indicator 1) were significantly more likely to provide good vision and comfort independently compared with spectacles that did not meet any indicator (good vision: 94.6 vs. 85.0%, P = .01; comfortable: 66.1 vs. 36.3%, P < .01). Adequately prescribed spectacles (indicator 2) were more likely to provide good comfort compared with spectacles not meeting any indicator (57.7 vs. 36.3%, P < .01); however, vision outcomes were not significantly different (85.9 vs. 85.0%, P = .90). Good vision was associated with a lower mean vector dioptric distance (P < .01) but not with comfort (P = .52). CONCLUSIONS The optimally prescribed spectacles indicator is a promising approach for assessing the quality of refractive error care without additional assessments of vision and comfort. Using USPs is a practical approach and could be used as a standardized method for evaluating the quality of refractive error care.

Uncorrected refractive error is the largest cause of global vision loss in 2020; 161 million people have distance vision impairment or blindness and 570 million people suffer from near vision impairment. Cataract (100 million people), age-related macular degeneration (8.1 million people), glaucoma (7.8 million people), and diabetic retinopathy (4.4 million people) are other leading causes of vision loss (Fig. 10.1). Uncorrected refractive error in South-East Asia (adjusted from the relevant Global Burden of Disease-defined regions to the World Health Organization (WHO)-defined South-East Asia Region, SEAR) accounted for 46.1% (95% CI: 42.19–49.51) of moderate to severe vision impairment (MSVI) and 12.6% (95% CI: 10.79–14.33%) of blindness [1]. Given that these data are for adults aged 50 years and above, the relative burden of vision impairment due to uncorrected refractive error is likely to be higher when data on younger adults and children are added.

BackgroundInformed decisions on myopia management require an understanding of financial impact. We describe methodology for estimating lifetime myopia costs, with comparison across management options, using exemplars in Australia and China.MethodsWe demonstrate a process for modelling lifetime costs of traditional myopia management (TMM=full, single-vision correction) and active myopia management (AMM) options with clinically meaningful treatment efficacy. Evidence-based, location-specific and ethnicity-specific progression data determined the likelihood of all possible refractive outcomes. Myopia care costs were collected from published sources and key informants. Refractive and ocular health decisions were based on standard clinical protocols that responded to the speed of progression, level of myopia, and associated risks of pathology and vision impairment. We used the progressions, costs, protocols and risks to estimate and compare lifetime cost of myopia under each scenario and tested the effect of 0%, 3% and 5% annual discounting, where discounting adjusts future costs to 2020 value.ResultsLow-dose atropine, antimyopia spectacles, antimyopia multifocal soft contact lenses and orthokeratology met our AMM inclusion criteria. Lifetime cost for TMM with 3% discounting was US$7437 (CI US$4953 to US$10 740) in Australia and US$8006 (CI US$3026 to US$13 707) in China. The lowest lifetime cost options with 3% discounting were antimyopia spectacles (US$7280, CI US$5246 to US$9888) in Australia and low-dose atropine (US$4453, CI US$2136 to US$9115) in China.ConclusionsFinancial investment in AMM during childhood may be balanced or exceeded across a lifetime by reduced refractive progression, simpler lenses, and reduced risk of pathology and vision loss. Our methodology can be applied to estimate cost in comparable scenarios.

Topic Presbyopia prevalence and spectacle-correction coverage were estimated by systematic review and meta-analysis of epidemiologic evidence, then modeled to expand to country, region, and global estimates. Clinical Relevance Understanding presbyopia epidemiologic factors and correction coverage is critical to overcoming the burden of vision impairment (VI) from uncorrected presbyopia. Methods We performed systematic reviews of presbyopia prevalence and spectacle-correction coverage. Accepted presbyopia prevalence data were gathered into 5-year age groups from 0 to 90 years or older and meta-analyzed within World Health Organization global burden of disease regions. We developed a model based on amplitude of accommodation adjusted for myopia rates to match the regionally meta-analyzed presbyopia prevalence. Presbyopia spectacle-correction coverage was analyzed against country-level variables from the year of data collection; variation in correction coverage was described best by a model based on the Human Development Index, Gini coefficient, and health expenditure, with adjustments for age and urbanization. We used the models to estimate presbyopia prevalence and spectacle-correction coverage in each age group in urban and rural areas of every country in the world, and combined with population data to estimate the number of people with near VI. Results We estimate there were 1.8 billion people (prevalence, 25%; 95% confidence interval [CI], 1.7–2.0 billion [23%–27%]) globally with presbyopia in 2015, 826 million (95% CI, 686–960 million) of whom had near VI because they had no, or inadequate, vision correction. Global unmet need for presbyopia correction in 2015 is estimated to be 45% (95% CI, 41%–49%). People with presbyopia are more likely to have adequate optical correction if they live in an urban area of a more developed country with higher health expenditure and lower inequality. Conclusions There is a significant burden of VI from uncorrected presbyopia, with the greatest burden in rural areas of low-resource countries.

PurposeWe used systematic review and meta-analysis to identify and assimilate evidence quantifying blindness and visual impairment (VI) associated with myopic macular degeneration (MMD), then derived models to predict global patterns. The models were used to estimate the global prevalence of blindness and VI associated with MMD from 2000 to 2050.MethodsThe systematic review identified 17 papers with prevalence data for MMD VI fitting our inclusion criteria. Data from six papers with age-specific data were scaled to relative age-dependent risk and meta-analysed at VI and blindness levels. We analysed variance in all MMD VI and blindness data as a proportion of high myopia against variables from the place and year of data collection, with a model based on health expenditure providing the best correlation. We used this model to estimate the prevalence and number of people with MMD VI in each country in each decade.ResultsWe included data from 17 studies comprising 137 514 participants. We estimated 10.0 million people had VI from MMD in 2015 (prevalence 0.13%, 95% CI 5.5 to 23.7 million, 0.07% to 0.34%), 3.3 million of whom were blind (0.04%, 1.8 to 7.8 million, 0.03% to 0.10%). We estimate that by 2050, without changing current interventions, VI from MMD will grow to 55.7 million people (0.57%, 29.0 to 119.7 million, 0.33% to 1.11%), 18.5 million of whom will be blind (0.19%, 9.6 to 39.7 million, 0.11% to 0.37%).ConclusionThe burden of MMD blindness and VI will rise significantly without efforts to reduce the development and progression of myopia and improve the management of MMD.

To further pursue potent Bax activators with better safety profiles for the treatment of breast cancer, structural optimization was conducted based on lead compound CYD-4-61 through several strategies, including scaffold hopping on the 2-nitro-fluorene ring, replacement of the nitro group with bioisosteres to avoid potential toxicity, and further optimization on the upper pyridine by exploring diverse alkylamine linkers as a tail or replacing the pyridine with bioisosteric heterocycles. F-containing compound 22d (GL0388) exhibited a good balance between the activity and toxicity, displaying submicromolar activities against a variety of cancer cell lines with 5.8–10.7-fold selectivity of decreased activity to MCF-10A human mammary epithelial cell line. Compound 22d dose-dependently blocked colony formation of breast cancer cells and prevented the migration and invasion of MDA-MB-231 cells. Mechanism of action studies indicate that 22d activated Bax, rendering its insertion into mitochondrial membrane, thereby leading to cytochrome c release from the mitochondria into the cytoplasm, subsequently inducing release of apoptotic biomarkers. Further in vivo efficacy studies of 22d in human breast cancer xenografts arisen from MDA-MB-231 cells demonstrated that this drug candidate significantly suppressed tumor growth, indicating the therapeutic promise of this class of compounds for the treatment of breast cancer as well as the potential for developing F-radiolabeled imaging ligands as anticancer chemical probes.

Breast cancer is one of the leading causes of cancer-related death in American women and the most common cancer in women with more than 270,000 estimated new cases in 2020 in the US. This is about 30% of the estimated total cancer patients in American women and therefore a major threat to the society with an urgent need of advanced treatment regimens. Especially the subgroup of estrogen receptor (ER)-negative breast cancers (ENBC), which are approximately one quarter to a third of all breast cancer, are lacking efficient treatment methods. Particularly dangerous is triple-negative breast cancer (TNBC), a subtype of ENBC with a high metastatic potential, since 90% of cancer-related deaths are due to metastasis. However, an effective drug for ENBC/TNCB treatment remains to be developed. The pro-apoptotic protein Bax was shown to be downregulated in most cancers. As a result, the balance between Bax and its antagonist Bcl-2 gets disturbed which leads to dysfunctional apoptotic signaling in favor of cancer cell survival. Upon activation, Bax is translocated from the cytosol to the mitochondria where it binds to the outer mitochondrial membrane. This leads to increased permeability of the mitochondrial membrane and a release of pro-apoptosis related molecules such as cytochrome C and others. Hence, drug discovery for Bax activation is a promising approach for developing novel cancer therapies. The small molecules GL0385 and GL0388 were identified from our progenitor molecules including small-molecule Bax activator (SMBA1), CYD-2-11, and CYD-4-61. The CYD compounds specifically target the Ser184 residue of Bax and have shown apoptosis-inducing effects both in vitro and in vivo. These lead Bax activators provided proof-of-concept studies while further optimization is needed to mitigate potential toxicity, leading to the discovery of advanced lead molecules GL0385 and GL0388. Treatment with either GL0385 or GL0388 resulted in significantly decreased cell proliferation in MDA-MB-231, MDA-MB-468, BT549, MDA-MB-453, MCF-7, and MDA-MB-361 cells. Additionally, MDA-MB-231 cells treated with GL0385 or GL0388 showed reduced migration and invasion, compared to control cells. Western blot analysis confirmed increased protein levels of Bax, cleaved PARP, cleaved caspase 3, and cytochrome C. These results show that GL0385 and GL388 have a significant impact on cancer cell proliferation and cellular motility which are main attributes of metastasizing cells. Additionally, increased expression of apoptosis markers indicates that these compounds may be beneficial to regain the anti-apoptotic/pro-apoptotic balance in breast cancer cells. Therefore, GL0385 and GL0388 are promising new advanced lead compounds towards the development of effective therapies for breast cancers and other cancers. Further investigation is warranted to fully explore their anti-cancer potential and mechanisms of action. Citation Format: Doerte R. Fricke, Hyejin Kim, Gang Liu, Haiying Chen, Jia Zhou, Qiang Shen. Putative Bax activators GL0385 and GL0388 for targeted breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1239.