Greater Potency Research Articles

Abstract LB317: Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations

Abstract Introduction: FGFRs play important roles in cancer development and inhibition of FGFR could disrupt tumor cell proliferation and growth. Four selective FGFR inhibitors have been approved (erdafitinib, pemigatinib, infigratinib, and futibatinib) and several others are in clinical development. Unfortunately upon treatment with these first-generation FGFR inhibitors, acquired resistance often develops and is frequently associated with the emergence of secondary FGFR2/3 kinase domain mutations. Therefore, selectively targeting FGFR2/3 as well as their resistant mutations may render a second-generation treatment approach for the refractory/relapsed patients. Using advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a novel, next-generation, and highly selective FGFR inhibitor, ABSK121. This novel inhibitor demonstrated robust anti-tumor activity in FGFR-dependent tumor models with strong activities against not only de novo but also acquired resistant mutations. Method: ABSK121 was evaluated in biochemical and cellular proliferation experiments for its inhibition on wile type FGFR enzymatic activity and FGFR-dependent cancer cell proliferation. Its potency against FGFR mutations was also analyzed in relevant biochemical and cellular experiments. Efficacy studies were conducted in multiple tumor models to confirm its in vivo activities. Preliminary selectivity profile and ADME profiles were also evaluated. Results: ABSK121 inhibited wild type FGFRs with IC50<10 nM in biochemical assay. ABSK121 also displayed great potency against resistant kinase domain mutations. In cell lines harboring FGFR amplification, fusions, or resistant mutations, ABSK121 demonstrated strong anti-proliferation activity as well as strong inhibition of FGFR downstream signaling activities. In preclinical in vivo studies, oral administration of ABSK121 strongly inhibited the growth of subcutaneous xenograft tumors dependent on wild type or resistant mutant FGFR. Suppression of tumor growth was dose-dependent and well correlated with pharmacodynamic inhibition of FGFR signaling. ABSK121 also showed great kinase selectivity with no CYP or hERG inhibition. Conclusion: ABSK121, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR inhibitor with great potency against resistant FGFR mutations. Its superior profile supports fast-track preclinical and clinical development. Citation Format: Haiyan Ying, Wenqun Xin, Haibing Deng, Yuan Zhao, Hongping Yu, Zhui Chen, Yao-chang Xu. Discovery and characterization of a next-generation FGFR inhibitor overcoming FGFR resistant mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB317.

Abstract 6217: Inhibiting ataxia-telangiectasia mutated and RAD3-related (ATR) by BAY 1895344 overcomes chemoresistance to oxaliplatin and promotes synergistic anti-tumor effect in pancreatic cancer

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive disease with a poor prognosis and a limited response to most of the treatments. Despite a platinum-based drug such as oxaliplatin or cisplatin is one of the most effective chemotherapy drugs for PDAC, resistance to it is a major limiting factor in PDAC treatment, indicating an urgent need for new approaches. Recently, targeting major DNA damage response (DDR) regulators such as ATM (Ataxia-telangiectasia mutated) or ATR (Ataxia telangiectasia mutated and Rad3-related) kinase has shown therapeutic potential in cancer treatment. This shows that it may be possible to enhance the responsiveness of platinum medicines via a DDR inhibition strategy. The most recently developed ATR inhibitor with the greatest potency, BAY 1895344, showed an anti-proliferative effect in clinical trials. Here, we aimed to evaluate the effect of ATR inhibition using BAY 1895344 on responsiveness to oxaliplatin in pancreatic cancer, for the first time. CFPAC-1 and Capan-2 are selected among six kinds of pancreatic cancer cell lines as oxaliplatin-sensitive and -resistant cells, respectively. According to BRAID analysis, combining the BAY 1895344 and oxaliplatin resulted in strong synergistic effects in both cell lines, particularly in Capan-2. The synergism is also confirmed in all four organoids derived from PDAC patients. We found that p-Chk1, coordinating DDR and cell cycle checkpoint, was considerably suppressed by the combined treatments, which was associated with elevated γ-H2AX intensity, cell cycle arrest and apoptosis. Moreover, we investigated the in vivo synergistic anti-tumor efficacy of combination therapy using a tumor-bearing nude mice model with CFPAC-1 and Capan-2 cells, demonstrating a substantial reduction of tumor growth in combination therapy when compared to single treatment. In conclusion, ATR inhibition enhanced the anticancer effect of oxaliplatin, and this combined therapeutic strategy may be effective in overcoming chemo-resistance in PDAC. (This study is supported by National Cancer Center, Republic of Korea (No. 2212470, 2010330)) Citation Format: Hye Won Shon, Jung Won Chun, Jeong Eun Gong, Mi Rim Lee, Yu-Sun Lee, Sumin Kang, Sunshin Kim, Sang Myung Woo, In Rae Cho, Woo Hyun Paik, Woo Jin Lee, Ji Kon Ryu, Yong-Tae Kim, Sang Hyub Lee, Yun-Hee Kim. Inhibiting ataxia-telangiectasia mutated and RAD3-related (ATR) by BAY 1895344 overcomes chemoresistance to oxaliplatin and promotes synergistic anti-tumor effect in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6217.

Abstract 1621: L105, a next generation of Bcl-2 inhibitor, overcomes Bcl-2 mutation and exhibits superior antitumor activity

Abstract Background: The Bcl-2 inhibitor venetoclax is approved for the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and acute myeloid leukemia (AML). However, disease progression occurs when Ventoclax long-term treatment as a single agent driven by the recurrent Bcl-2 mutations, such as G101V, D103Y, D103E, et al. Here, we described the discovery of a next generation Bcl-2 inhibitor L105 with high potency against Bcl-2, Bcl-2(G101V) and Bcl-2(D103Y) for treatment of Bcl-2 dependent and venetoclax resistant hematological cancers. Methods: Biochemical inhibition assays were conducted by TR-FRET based assay. Proliferation inhibition assays on a panel of hematologic tumor cells were carried out by MTS assay. Caspase-3 activation in RS4;11 was determined by western blot. Preclinical pharmacokinetics studies were assayed in mice and dogs and parameters were determined by LC-MS. In vivo pharmacodynamic studies were performed in RS4;11 and OCI-LY10 derived xenograft SCID mouse models. In vitro human platelet toxicity was measured by CellTiter-Glo assay. Cytochrome P450 inhibition was measured in fluorometric assay. Results: In biochemical assays, the IC50 of L105 against Bcl-2 WT, Bcl-2 G101V, Bcl-2 D103Y, Bcl-2 D103E with IC50 of 0.42, 0.83, 0.97 and 5.78 nM respectively,while those of venetoclax were 1.89, 704.27, 470.19 and 243.30 nM respectively. In cellular assays, the IC50 of L105 in RS4;11, RS4;11 overexpressing Bcl-2 G101V, OCI-LY10, MV4-11, Mino, Toledo, Maver-1, SU-DHL-6 and REC-1 were 0.30-243.36 nM, while those of venetoclax were 2.91-3360.79 nM. L105 showed >2000 folds Bcl-2 selectivity over Bcl-xL. Furthermore, in vitro platelet viability assay showed L105 induced hypotoxicity at similar level of venetoclax. In pharmacodynamics studies, 5mpk L105 induced more rapid and robust antitumor effect in RS4;11 xenograft than venetoclax at 10 mpk did, and 15mpk L105 showed significant longer and stronger tumor suppression response than venetoclax at 25 mpk did. In the preclinical pharmacokinetic (PK) studies, L105 showed excellent PK properties in ICR mice and beagle dogs, in terms of long T1/2 and high dose-normalized AUC. L105 also exhibited a less drug-drug interaction potential, as no evidence on CYPs inhibition (IC50 >20 μM), while venetoclax potently inhibited CYP2C9 with IC50 at 1.12 μM. In 14-days oral gavage toxicity study in mice, no compound related deaths occurred at 15, 50 and 300 mpk, and only leukopenia was observed at similar level of venetoclax. Conclusions: L105 showed great potency on wild type and acquisition resistance mutations of Bcl-2, excellent oral bioavailability, and superior preclinical anti-tumor activities and safety profiles. It may provide new thoughts on treatment for a wide range of Bcl-2-dependent and Venetoclax-resistant hematological cancers. Citation Format: Xingguo Liu, Yang Lou, Yizhe Wu, Mingbo Su, Anhui Gao, Jinglai Huang, Li Zhong, Xinglu Zhou. L105, a next generation of Bcl-2 inhibitor, overcomes Bcl-2 mutation and exhibits superior antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1621.

MP60-12 CHIMERIC BOTULINUM NEUROTOXIN A-B HAS HIGHER NEUROMUSCULAR BLOCKADE POTENCY COMPARED TO BOTULINUM NEUROTOXIN A IN THE MOUSE BLADDER

You have accessJournal of UrologyCME1 Apr 2023MP60-12 CHIMERIC BOTULINUM NEUROTOXIN A-B HAS HIGHER NEUROMUSCULAR BLOCKADE POTENCY COMPARED TO BOTULINUM NEUROTOXIN A IN THE MOUSE BLADDER Hatim Thaker, Jie Zhang, Rosalyn Adam, Vivian Cristofaro, Maryrose Sullivan, and Min Dong Hatim ThakerHatim Thaker More articles by this author , Jie ZhangJie Zhang More articles by this author , Rosalyn AdamRosalyn Adam More articles by this author , Vivian CristofaroVivian Cristofaro More articles by this author , Maryrose SullivanMaryrose Sullivan More articles by this author , and Min DongMin Dong More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003318.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Neurogenic and idiopathic detrusor overactivity (DO) is currently treated with onabotulinumtoxin A (onaBoNT/A) as third-line therapy. However, BoNT/A requires repeated injections into the bladder and is known to have diminished treatment effect after 5 years. Novel, chimeric toxins may provide an alternative to BoNT/A in the setting of treatment failure. Chimeric BoNT/A-B is a construct that consists of the light chain (catalytic domain) of BoNT/A, paired with a receptor binding domain of BoNT/B. This receptor binding domain binds to synaptotagmin-1, recently shown to be the dominant BoNT receptor in the bladder. Here, we aim to determine the effect of a chimeric BoNT/A-B construct in mouse bladder tissues. METHODS: Gene fragments encoding the light chain and translocation domain of BoNT/A, as well as the receptor binding domain for BoNT/B, were produced via PCR and cloned into a vector to produce chimeric BoNT/A-B. To assess ex vivo smooth muscle response, wild type (WT) mouse bladders were harvested and placed in Kreb's buffer. Each bladder was cut into three longitudinal strips and mounted in tissue chambers at 37 C with continuous bubbled mixture of carbogen. Bladder strips were attached to a force transducer (Figure A) and underwent nerve-evoked contraction studies via electrical field stimulation (EFS; 1-64Hz, 30V 0.5 ms pulse width, 10 sec duration), with the addition of 0.3 or 1 nM BoNT/A-B, to generate a frequency response curve. RESULTS: Ex vivo contraction studies in the presence of 1 nM BoNT/A-B showed a reduction in 80% of nerve-evoked contractions by 100 minutes; BoNT/A had produced the same degree of reduction at only 300 minutes, reflecting the rapid onset of BoNT/A-B. At a lower dose of 0.3 nM, BoNT/A-B reduced nerve-evoked contractions by 40% at 100 minutes; BoNT/A had minimal effect (Figure B). All bladder weights were similar, and data were normalized to the cross-sectional area of the bladder strip. Carbachol dose-response curves served as controls to ensure bladder strips were viable and contractile pre- and post-exposure. CONCLUSIONS: We demonstrate chimeric BoNT/A-B has a faster onset and great potency at lower doses in smooth muscle ex vivo. This novel toxin may provide improved neuromuscular paralysis smooth muscle disorders, such as overactive and neurogenic bladder. Source of Funding: H.T. is supported by the NIH T32 Grant, AUA Urology Care Foundation Research Scholar Award, the SUFU Chemodenervation Grant, and the Office of Faculty Development at Harvard Medical School. M.D. is supported by grants from the NIH and holds the Investigator in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Fund. M.P.S. received support from the U.S. Department of Veterans Affairs © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e848 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hatim Thaker More articles by this author Jie Zhang More articles by this author Rosalyn Adam More articles by this author Vivian Cristofaro More articles by this author Maryrose Sullivan More articles by this author Min Dong More articles by this author Expand All Advertisement PDF downloadLoading ...

Safety and tolerability of esketamine in propofol based sedation for endoscopic variceal ligation with or without injection sclerotherapy: Randomized controlled trial.

Esketamine is an S (+) enantiomer of ketamine with greater potency and similar psychomimetic effects compared to racemic ketamine. We aimed to explore the safety of esketamine in different doses as an adjuvant to propofol in patients undergoing endoscopic variceal ligation (EVL) with or without injection sclerotherapy. One hundred patients were randomized to receive sedation with propofol 1.5 mg/kg in combination with sufentanil 0.1 μg/kg (group S), esketamine 0.2 mg/kg (group E0.2), esketamine 0.3 mg/kg (group E0.3), or esketamine 0.4 mg/kg (group E0.4) for EVL (n=25 each). Hemodynamic and respiratory parameters were recorded during the procedure. The primary outcome was the incidence of hypotension; secondary outcomes included the incidence of desaturation, positive and negative syndrome scale (PANSS) after the procedure, pain score after the procedure, and secretion volume. The incidence of hypotension was significantly lower in groups E0.2 (36%), E0.3 (20%), and E0.4 (24%) than in group S (72%). The incidence of SpO2 ≤94% was significantly lower in group E0.4 (4%) than in group S (32%). No significant intergroup difference was found in the PANSS assessment. Combining 0.4 mg/kg esketamine with propofol sedation was optimal to facilitate EVL with stable hemodynamic status and better respiratory function during the procedure, without significant psychomimetic side-effects. Chinese Clinical Trial Registry (Trial ID: ChiCTR2100047033, http://www.chictr.org.cn/showproj.aspx?proj=127518).

Design, synthesis and neuraminidase inhibitory activity of 4-methyl-5-(3-phenylacryloyl) thiazoles.

A series of 4-methyl-5-(3-phenylacryloyl)thiazoles based on chalcones were designed, synthesized and evaluated for their influenza neuraminidase (NA) inhibitory activity in vitro. A preliminary structure-activity relationship (SAR) analysis showed that thiazoles bearing amide had greater potency. It also showed that mono-hydroxyl group at 4-position on phenyl ring was more effective than other electron-releasing groups or electron-withdraw groups. Compounds A2 and A26 were more potent against NA with IC50 values of 8.2 ± 0.5μg/mL and 6.2 ± 1.4μg/mL, respectively. Molecular docking study demonstrated that thiazoles skeleton was benefit for the NA inhibitory activity.

Antagonistic effect of mepyramine and tubocurarine on the histamine-mediated contraction of intestinal smooth muscle cells

Introduction: Histamine is an endogenous ligand which exerts its biological actions by binding to 4 subtypes of histamine receptors (HR). Its effects on the gastrointestinal tract are complex being the dominant effect contraction of muscle cells.
 Method: The aim of this study was to verify the antagonistic effect of mepyramine (10-10M - 10-7M) and tubocurarine (10-7M - 10-4M) in the contractile action of histamine (10-11M - 10-4M). in guinea pig ileum, for this purpose it was used the program Virtual Organ Bath 16 V 2.8, which allow quantify the change in strength(g) produced by smooth muscle contraction in the presence of these substances. Concentration-response curves were obtained through GraphPad Prism® graphic program. The determination of the competitive nature of the antagonist and the calculation of the affinity constant was performed through Schild method.
 Results: Mepyramine is a competitive antagonist of histamine (10-10M to 10-7M), making it a potential therapeutic agent for the treatment of irritable bowel syndrome. On the other hand, it is not understood that tubocurarine is an antagonist of histamine receptors.
 Conclusions: The results obtained provide evidence that the contractile effect of histamine on the smooth muscle of intestinal cells isolated from guinea pig is competitively antagonized by mepyramine. In addition, by calculating the pKB parameter, it was found that this compound has greater potency than other antihistamines.

An extended interval between vaccination and infection enhances hybrid immunity against SARS-CoV-2 variants.

As the COVID-19 pandemic continues, long-term immunity against SARS-CoV-2 will be globally important. Official weekly cases have not dropped below 2 million since September of 2020, and continued emergence of novel variants have created a moving target for our immune systems and public health alike. The temporal aspects of COVID-19 immunity, particularly from repeated vaccination and infection, are less well understood than short-term vaccine efficacy. In this study, we explore the impact of combined vaccination and infection, also known as hybrid immunity, and the timing thereof on the quality and quantity of antibodies elicited in a cohort of 96 health care workers. We find robust neutralizing antibody responses among those with hybrid immunity against all variants, including Omicron BA.2, and significantly improved neutralizing titers with longer vaccine-infection intervals up to 400 days. These results indicate that anti-SARS-CoV-2 antibody responses undergo continual maturation following primary exposure by either vaccination or infection for at least 400 days after last antigen exposure. We show that neutralizing antibody responses improved upon secondary boosting with greater potency seen after extended intervals. Our findings may also extend to booster vaccine doses, a critical consideration in future vaccine campaign strategies.

Design, synthesis, and antitumor evaluation of morpholine substituted bisnaphthalimides as DNA targeting agents

A series of mono- and bisnaphthalimides derivatives containing 3-nitro and 4-morpholine moieties were designed, synthesized, and evaluated for their in vitro anticancer activities against four cancer cell lines. Some compounds exhibited relatively good antiproliferative activity on the cell lines tested, in comparison with mitonafide and amonafide. It is noteworthy that bisnaphthalimide A6 was identified as the most potent compound in anti-proliferation against MGC-803 cells, with an IC50 lowered to 0.09 μM, a far greater potency than that of mono-naphthalimide A7, mitonafide, and amonafide. A gel electrophoresis assay revealed that DNA and Topo I were the potential targets of compounds A6 and A7. The treatment of CNE-2 cells with compounds A6 and A7 resulted in an S phase cell cycle arrest, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of CDK2 and cyclin E. In addition, compounds A6 and A7-induced apoptosis was further confirmed by flow cytometry, ROS generation assay, and Hoechst 33,258 staining. In particular, in vivo antitumor assay results revealed that bisnaphthalimide A6 exhibited potent anticancer efficiency in an MGC-803 xenograft tumor model, in comparison with mitonafide, and had lower toxicity than mono-naphthalimide A7. In brief, the results suggested that bisnaphthalimide derivatives containing 3-nitro and 4-morpholine moieties might serve as DNA binding agents for the development of new antitumor agents.

Doxorubicin-loaded liposomes surface engineered with the matrix metalloproteinase-2 cleavable polyethylene glycol conjugate for cancer therapy

BackgroundColorectal cancer is one of the prominent leading causes of fatality worldwide. Despite recent advancements within the field of cancer therapy, the cure rates and long-term survivals of patients suffering from colorectal cancer have changed little. The application of conventional chemotherapeutic agents like doxorubicin is limited by some drawbacks such as cardiotoxicity and hematotoxicity. Therefore, nanotechnology has been exploited as a promising solution to address these problems. In this study, we synthesized and compared the anticancer efficacy of doxorubicin-loaded liposomes that were surface engineered with the 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-matrix metalloproteinase-2 (MMP-2) cleavable peptide-polyethylene glycol (PEG) conjugate. The peptide linker was used to cleave in response to the upregulated MMP-2 in the tumor microenvironment, thus exposing a positive charge via PEG-deshielding and enhancing liposomal uptake by tumor cells/vasculature. Liposomal formulations were characterized in terms of size, surface charge and morphology, drug loading, release properties, cell binding and uptake, and cytotoxicity.ResultsThe formulations had particle sizes of ~ 100–170 nm, narrow distribution (PDI ˂ 0.2), and various surface charges (− 10.2 mV to + 17.6 mV). MMP-2 overexpression was shown in several cancer cell lines (C26, 4T1, and B16F10) as compared to the normal NIH-3T3 fibroblast cells by gelatin zymography and qRT-PCR. In vitro results demonstrated enhanced antitumor efficacy of the PEG-cleavable cationic liposomes (CLs) as compared to the commercial Caelyx® (up to fivefold) and the chick chorioallantoic membrane assay showed their great antiangiogenesis potential to target and suppress tumor neovascularization. The pharmacokinetics and efficacy studies also indicated higher tumor accumulation and extended survival rates in C26 tumor-bearing mice treated with the MMP-2 cleavable CLs as compared to the non-cleavable CLs with no remarkable sign of toxicity in healthy tissues.ConclusionAltogether, the MMP-2-cleavable CLs have great potency to improve tumor-targeted drug delivery and cellular/tumor-vasculature uptake which merits further investigation.

Photodynamic nano hydroxyapatite with biofilm penetration capability for dental plaque eradication and prevention of demineralization

Dental caries represents one of the most prevalent diseases worldwide, characteristic of the growth of dental plaque and demineralization of tooth enamel. Current medications for eradication of dental plaques and prevention of demineralization suffer from several limitations to overcome, calling for novel strategies with great potency in eliminating cariogenic bacteria and dental plaque that forms, as well as in inhibiting the demineralization of enamel, into an integrated system. Considering the potency of photodynamic therapy in bacteria inactivation and the composition of enamel, we herein report that the novel photodynamic nano hydroxyapatite (nHAP), named Ce6 @QCS/nHAP, was useful for this purpose. Ce6 @QCS/nHAP, comprised of quaternary chitosan (QCS)-coated nHAP loaded with chlorin e6 (Ce6), exhibited good biocompatibility and non-compromised photodynamic activity. In vitro studies revealed that Ce6 @QCS/nHAP could effectively associate with cariogenic Streptococcus mutans (S. mutans), leading to a significant antibacterial effect through photodynamic killing and physical inactivation against the planktonic microbe. Three-dimensional fluorescence imaging suggested that Ce6 @QCS/nHAP exhibited a superior S. mutans biofilm penetration capacity to free Ce6, resulting in effective dental plaque eradiation when light irradiation was applied. The number of surviving bacteria in biofilm was at least 2.8 log units lower in the Ce6 @QCS/nHAP group compared to that in the free Ce6 group. Further, in the S. mutans biofilm-infected artificial tooth model, treatment with Ce6 @QCS/nHAP also resulted in the significant prevention of hydroxyapatite disks from demineralization, with lower percentage of fragmentation and weight loss These data suggest that our photodynamic nanosystem can effectively eradicate dental plaque while also significantly protecting artificial tooth from demineralization, opening up new possibilities in treating bacterium-associated dental caries.

The Failure of Language Amidst the Joy of Grace

For Clarice Lispector, language is a sacrament on dazzling display in her work, where the celebration of writing and the emergence of a creative consciousness through the act of writing about writing access an immanent experience of grace beyond any historical religious sensibility. In this, she simultaneously accesses the “great potency of potentiality” that is an experience of freedom undoing anything bound up by language. She embraces the failure of language as the “glory of falling,” the useless experience of grace, and of experiencing the gift of having a body beyond whatever words we can place upon it. In the struggle to behold the “it” underneath language, she strives for an impersonal love – a joy – that respects the inviolability of nature, the “Force of what Exists and that is sometimes called God.” If “the absence of the God is an act of religion,” as she claims, the inviolability of nature is that which preserves an experience of immanent grace in our world. Rather than describe the limitless potential of the self, one’s immersion in the joyful failure of language points toward the self in unique and profound ways without offering definitions, instead allowing internal contradictions to condition one’s selfhood. In Lispector’s fiction we thus confront the pure paradox of the self: an internal, singular individual who yet maintains within themselves (hence, its immanence) a plurivocal affirmation of existence itself and a redefining of God.

PROTACs: Walking through hematological malignancies.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that uses the proteasome ubiquitin system to target proteins of interest and promote their degradation with remarkable selectivity. Importantly, unlike conventional small molecule inhibitors, PROTACs have proven highly effective in targeting undruggable proteins and those bearing mutations. Because of these considerations, PROTACs have increasingly become an emerging technology for the development of novel targeted anticancer therapeutics. Interestingly, many PROTACs have demonstrated a great potency and specificity in degrading several oncogenic drivers. Many of these, following extensive preclinical evaluation, have reached advanced stages of clinical testing in various cancers including hematologic malignancies. In this review, we provide a comprehensive summary of the recent advances in the development of PROTACs as therapeutic strategies in diverse hematological malignancies. A particular attention has been given to clinically relevant PROTACs and those targeting oncogenic mutants that drive resistance to therapies. We also discus limitations, and various considerations to optimize the design for effective PROTACs.

In Vivo PAkt Detection and in Silico Molecular Docking to Determine the Potential of BYL as an PI3K Inhibitor to Block Growth Signal Cascade and in Breast Cancer MCF Cell Line

Comparison of genome between normal and breast cancer cell line shows that there are mutations across PI3Ka that probably cause breast cancer. PI3Ka is a kinase that plays a significant role in cell signalling transduction by phosphorylation cascade and produce an effect on cell. SH2 domain on PI3Ka binds to activated phosphor-tyrosine amino acids in growth factors, activating PI3Ka p110 catalytic domain, which recruits PIP2 to membrane and phosphorylates it to PIP3. This leads to cell signalling outcomes, including activation of PDK which phosphorylates Akt, cell proliferation and death. Protein/lipid phosphorylation levels are tightly controlled by phosphorylases and kinases; therefore, transduction levels can be turned on/off via altering kinases or phosphorylases and PI3K can be a target for treating breast cancer. However, we need find out which PI3K inhibitor (A66, TGX and unknown inhibitor BYL) shows that greatest potency and efficacy against PI3Ka with respect to pAkt in MCF-7 cell line. Here we show BYL has the potential to be a PI3Ka inhibitor and all of them inhibit pAkt. Using in silico technique of molecular docking, we explain that BYL shows the same amount of four hydrogen bonds as A66. By carrying out an experiment that generate a concentration-response curve, we demonstrate that BYL has the highest potency and efficacy with respect to pAkt level among the three inhibitors, greater than A66 which is known previously to be a potent and efficacy PI3Ka inhibitor. Our results demonstrate BYL and A66 show higher potency and efficacy than TGX; TGX with less hydrogen bonds between drug-protein interactions reveals lower potency and efficacy. Our assay accessed the inhibition of pAkt caused by three PI3Ka inhibitors (A66, TGX and BYL) in breast cancer cell line MCF-7 and found out that tumour derived stimulation of pAkt were responsive to all three inhibitors with BYL exhibits the greatest inhibition, followed by A66 and TGX in vivo due to different drug-protein interaction. Furthermore, PI3Ka inhibition has the potential to block growth signalling cascade in breast cancer and is a major target of anti-breast cancer development.

Identification of cancer protein biomarker based on cell specific peptide and its potential role in predicting tumor metastasis

The identification of tumor related membrane protein is important for both cancer diagnosis and targeted therapy. Currently, the number of ideal clinical biomarkers is still limited partially because of lacking efficient methods in biomarker discovery. Targeting peptides are generated by library screening and can recognize their cognate targets with high specificity and affinity. In addition, these functional peptides have been considered to be a valuable molecule for both imaging detection and targeting therapy in oncology. The selected peptides can be used to identify cell-surface protein biomarkers of cancer cells. In our study, the peptide (VECYLIRDNLCIY) derived from the bacteria displaying library worked as a bait to capture its binding partner and aldolase A was identified as the candidate. The results indicated that aldolase A' expression level on the cell membrane was regulated by PI3K and aldolase A located on the membrane could inhibit the aggression of tumors through mediating cell metabolic pathway. Aldolase A could work as the joint for the metabolic and signal pathways related to tumor progression. In our work, we demonstrated a promising technology for selecting and identifying binding partners for cell-specific peptides that enables discovery of new tumor biomarkers, showing great scientific study values and clinical translation potencies. SignificanceMS-based cancer biomarker discovery provides promising target candidates for cancer diagnosis and therapy. However, the inevitable limits make it inconvenient in the process of sample preparation and data analysis. In this way, the small molecular probes show some advantages due to their readily availability and specific binding affinity such as the aptamers screened with SELEX technology and peptides derived from displaying libraries. In the present study, aldolase A was proved to be the membrane binding partner of a specific peptidic ligand towards ZR-75-1 tumor cell. It was discovered that membrane aldolase A was more sensitive and observable than other subcellular fractions in response to cellular metabolic state alteration or glucose availability. In addition, the reduced membrane-localized aldolase A expression indicated a more aggressive tumor phenotype and was accompanied by the upregulation of MMP-2/MMP-9. The non-glycolysis activity endowed it with potential utility as a tumor diagnostic marker and therapeutic target. This work demonstrates the practicability of screened peptide in cancer biomarker discovery, facilitating the development of diagnostic tools and therapeutic approaches to cancer, and markedly improves our understanding of cancer biology,

Potential Impact of Non-Steroidal Mineralocorticoid Receptor Antagonists in Cardiovascular Disease.

Inappropriate mineralocorticoid receptor (MR) activation in different cardiovascular cell types has deleterious effects on cardiac remodeling and function. Therefore, MR inhibition is a crucial pharmacological strategy to overcome cardiovascular dysfunction. Despite efficient blockade of MR with steroidal MR antagonists (MRAs), their clinical application is unsatisfactory due to the adverse effects. Newer non-steroidal MRAs with greater potency could be suitable for clinical application, especially in patients with type 2 diabetes mellitus and chronic kidney disease. Although clinical evidence has shown the beneficial effects of non-steroidal MRAs on cardiovascular outcomes in patients with heart failure with reduced ejection fraction, clinical trials are ongoing to evaluate the efficacy of heart failure with preserved ejection fraction. Therefore, comparative pharmacological characterization of non-steroidal MRAs over classic steroidal MRAs is crucial. Here, we summarize the pre-clinical evidence of non-steroidal MRAs, which suggests an improvement in cardiac dysfunction, as well as the underlying molecular mechanisms in animal models mimicking different clinical conditions. In addition, we discuss up-to-date information from clinical trials regarding the beneficial effects of non-steroidal MRAs on meaningful cardiovascular outcomes. Both pre-clinical and clinical evidence support treatment with non-steroidal MRAs in patients with cardiovascular disease.

Multi-target activity of copper complexes: Antibacterial, DNA binding, and molecular docking with SARS-CoV-2 receptor

A series of pendant-armed mixed-ligand copper(II) complexes of the type [CuL1-3(diimine)] (1–6) have been synthesized by the reaction of pendant-armed ligands N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)benzamide (H2L1), N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)-4-nitrobenzamide (H2L2) and N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)-3,5-dinitrobenzamide (H2L3) with diimine = 2,2′-bipyridyl (bpy) or 1,10-phenanthroline (phen) in the presence of copper(II) chloride and analyzed using various spectroscopic methods. All the spectroscopic results support that the complexes adopt a pentagonal-bipyramidal shape around the copper ion. Gram-positive and Gram-negative bacteria were used to test all the complexes for antibacterial activity and all the complexes had greater potency against gram-negative pathogens. DNA-binding experiments of complexes with calf thymus DNA revealed a major-groove binding pattern, further supported by molecular docking studies. Complexes have significantly interacted with SARS-CoV-2 receptor via π-π, π-σ, π-alkyl, π-anion, π-cation, alkyl, hydrogen bond, van der Waals, and electrostatic interactions. The estimated binding energy and inhibition constant of these complexes are higher than standard drugs, chloroquine, and molnupiravir.

Inhibiting COX-2/PGE2 pathway with biodegradable NIR-Ⅱ fluorescent polymeric nanoparticles for enhanced photodynamic immunotherapy

Photodynamic therapy (PDT) capable of eliciting antitumor immune responses by inducing immunogenic cell death (ICD) holds promise for tumor suppression. However, most photosensitizers suffer from limited degradation, insufficient biocompatibility, and inabilities to generate long-wavelength fluorescence for in vivo tracking. Moreover, PDT has the inherent problem of activating the cyclooxygenase-2/prostaglandin-E2 (COX-2/PGE2) pathway and upregulating programmed cell death ligand 1 (PD-L1) expression, resulting in insufficient efficacy of photodynamic immunotherapy. Herein, we designed and synthesized a dihydroxy-containing BODIPY monomer (MonoBodipy), and then formed the biodegradable polymer (PPDT) by polycondensation reaction, which could generate reactive oxygen species (ROS) for photodynamic immunotherapy and emit near-infrared-Ⅱ (NIR-Ⅱ) fluorescence for bioimaging. Subsequently, we further utilized PPDT to encapsulate the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) to form NPPDT@CXB that could inhibit the COX-2/PGE2 pathway. NPPDT@CXB displayed great anticancer potency on osteosarcoma and ovarian cancer in vitro. Further, NPPDT@CXB could accumulate at tumor site after intravenous administration into tumor-bearing mice, generate ROS, induce ICD cascade, and trigger antitumor immune responses under an 808 nm laser irradiation. The ROS further breaks up thioketal linkages in PPDT, resulting in a rapid CXB release to inhibit the COX-2/PGE2 pathway and then downregulate the PD-L1 expression in tumor cells, which in turn leads to an effective suppression of the primary and distant tumors. This work highlighted a well biocompatible and biodegradable photosensitizer that generates ROS, emits long-wavelength fluorescence, inhibits the COX-2/PGE2 pathway, and downregulates PD-L1 expression simultaneously, exhibiting a robust photodynamic immunotherapy efficacy. This study proposed a new strategy to overcome the inherent problems of photodynamic immunotherapy and pointed out the path of future PDT development.

Evaluation of seasonal variation in Veerya of visha dravya Kuchala

Introduction - Medicinal plants, as well as poisonous plants, have different alkaloid compositions in every season. According to the traditional texts of Ayurveda, Visha Dravya have greater potency in Varsha Ritu, which reduces due to Agasti rising in Sharad Ritu. Objective - To evaluate the potency of Visha in Varsha and Sharad Ritu through estimation of the concentration of Strychnine in Strychnos nux- vomica L. Materials and Methods – Quantitative analysis of Strychnine in Varsha and Sharad Ritu by HPTLC. Results – The concentration of Strychnine was observed higher in Varsha Ritu than in Sharad Ritu. Conclusion – The study confirms that the potency of Visha is greater in Varsha Ritu than in Sharad Ritu.

Plant Leaf Disease Detection and Classification Using Deep Learning: A Review and A Proposed System on Bangladesh’s Perspective

A very crucial part of Bangladeshi people’s employment, GDP contribution, and mainly livelihood is agriculture. It plays a vital role in decreasing poverty and ensuring food security. Plant diseases are a serious stumbling block in agricultural production in Bangladesh. At times, humans can’t detect the disease from an infected leaf with the naked eye. Using inorganic chemicals or pesticides in plants when it’s too late leads in vain most of the time, deposing all the previous labor. The deep-learning technique of leaf-based image classification, which has shown impressive results, can make the work of recognizing and classifying all diseases trouble-less and more precise. In this paper, we’ve mainly proposed a better model for the detection of leaf diseases. Our proposed paper includes the collection of data on three different kinds of crops: bell peppers, tomatoes, and potatoes. For training and testing the proposed CNN model, the plant leaf disease dataset collected from Kaggle, is used which has 17430 images. The images are labeled with 14 separate classes of damage. The developed CNN model performs efficiently and could successfully detect and classify the tested diseases. The proposed CNN model may have great potency in crop disease management.