Publications by authors named "Victor S Lin"

8 Publications

  • Page 1 of 1

BH3 Mimetics for the Treatment of B-Cell Malignancies-Insights and Lessons from the Clinic.

Cancers (Basel) 2020 Nov 12;12(11). Epub 2020 Nov 12.

The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, 3052 Parkville, Australia.

The discovery of the link between defective apoptotic regulation and cancer cell survival engendered the idea of targeting aberrant components of the apoptotic machinery for cancer therapy. The intrinsic pathway of apoptosis is tightly controlled by interactions amongst members of three distinct subgroups of the B-cell lymphoma 2 (BCL2) family of proteins. The pro-survival BCL2 proteins prevent apoptosis by keeping the pro-apoptotic effector proteins BCL2-associated X protein (BAX) and BCL2 homologous antagonist/killer (BAK) in check, while the BH3-only proteins initiate apoptosis by either neutralizing the pro-survival BCL2 proteins or directly activating the pro-apoptotic effector proteins. This tripartite regulatory mechanism is commonly perturbed in B-cell malignancies facilitating cell death evasion. Over the past two decades, structure-based drug discovery has resulted in the development of a series of small molecules that mimic the function of BH3-only proteins called the BH3 mimetics. The most clinically advanced of these is venetoclax, which is a highly selective inhibitor of BCL2 that has transformed the treatment landscape for chronic lymphocytic leukemia (CLL). Other BH3 mimetics, which selectively target myeloid cell leukemia 1 (MCL1) and B-cell lymphoma extra large (BCLxL), are currently under investigation for use in diverse malignancies. Here, we review the current role of BH3 mimetics in the treatment of CLL and other B-cell malignancies and address open questions in this rapidly evolving field.
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http://dx.doi.org/10.3390/cancers12113353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696913PMC
November 2020

BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax.

Blood 2020 06;135(25):2266-2270

Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Highly active BTK inhibitors (BTKis) and the BCL2 inhibitor venetoclax have transformed the therapeutic landscape for chronic lymphocytic leukemia (CLL). Results of prospective clinical trials demonstrate the efficacy of venetoclax to salvage patients with disease progression on BTKis, but data on BTKi therapy after disease progression on venetoclax are limited, especially regarding durability of benefit. We retrospectively evaluated the records of 23 consecutive patients with relapsed/refractory CLL who received a BTKi (ibrutinib, n = 21; zanubrutinib, n = 2) after stopping venetoclax because of progressive disease. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 34 months (range, <1 to 49) and 42 months (range, 2-49), respectively. Prior remission duration ≥24 months and attainment of complete remission or undetectable measurable residual disease on venetoclax were associated with longer PFS after BTKi salvage (P = .044 and P = .029, respectively). BTKi therapy achieved durable benefit for patients with the BCL2 Gly101Val venetoclax resistance mutation (estimated 24-month PFS, 69%). At a median survivor follow-up of 33 months (range, 2-53), 11 patients remained on BTKi and 12 had stopped therapy because of disease progression (n = 8) or toxicity (n = 4). Our findings indicate that BTKi therapy can provide durable CLL control after disease progression on venetoclax.
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http://dx.doi.org/10.1182/blood.2020004782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316215PMC
June 2020

Undetectable peripheral blood MRD should be the goal of venetoclax in CLL, but attainment plateaus after 24 months.

Blood Adv 2020 01;4(1):165-173

Department of Clinical Haematology, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, Australia.

The highly selective BCL2 inhibitor venetoclax achieves deep responses in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), including undetectable minimal residual disease (uMRD). We retrospectively reviewed 62 patients with CLL treated with venetoclax to investigate the performance of peripheral blood (PB) compared with bone marrow (BM) assessment of MRD; the kinetics, clinicopathological associations, and longer-term outcomes of uMRD attainment and recrudescence; and the ability of venetoclax dose escalation to deepen responses. Among 16 patients who achieved PB uMRD and had contemporaneous BM assessments, 13 (81%) had confirmed BM uMRD, and patients with PB uMRD had outcomes at least as favorable as those with BM uMRD for time to progression, overall survival, and MRD recrudescence. Excluding 2 patients lacking earlier assessment, the median time to PB uMRD was 18 (range, 5-26) months, with 90% of instances achieved by 24 months. There was no new PB uMRD attainment after 24 months without treatment intensification. The dominant association with earlier attainment of uMRD was concurrent rituximab (P = .012). Complex karyotype was associated with inferior uMRD attainment after 12 months of therapy (P = .015), and patients attaining uMRD whose disease harbored TP53 abnormalities demonstrated a trend toward earlier recrudescence (P = .089). Of patients who received venetoclax dose escalations, 4 (27%) of 15 achieved improvements in response. For patients with R/R CLL receiving venetoclax, PB uMRD commonly correlates with BM uMRD and is associated with a comparable longer-term prognosis. Concurrent rituximab augments uMRD attainment, but dose escalation and further treatment beyond 24 months infrequently deepen responses.
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http://dx.doi.org/10.1182/bloodadvances.2019000864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960473PMC
January 2020

Older adult consumers' attitudes and preferences on electronic patient-physician messaging.

Am J Manag Care 2013 Nov;19(10 Spec No):eSP7-11

David Geffen School of Medicine at UCLA, Department of Medicine, Division of Geriatrics, 10945 Le Conte Ave, Ste 2339, Los Angeles, CA 90095. E-mail:

Objective: To evaluate and compare the attitudes and preferences of younger and older adults regarding health information exchange with providers, and identify barriers and limitations to meaningful use.

Study Design: Cross-sectional study.

Methods: Qualitative and quantitative data gathered from online surveys of younger and older adult patients enrolled in a freestanding, Internetbased patient-physician messaging system that requires an individual account. This messaging system is only a secure messaging center, and does not allow for direct access to personal medical records.

Results: Data were collected from 324 patients (or proxy users) who reported their age, with 55.2% of respondents under the age of 65 years (mean age 48.2 years) and 44.8% of respondents 65 years or older (mean age 74.9 years). Family and non-family caregivers (proxy users) (mean age 59.2 years) comprised 21.0% of respondents. Overall, 83.9% of all respondents preferred to communicate with the provider via e-mail, and 84.5% of users found the messaging system easy to use, with a majority utilizing the messaging system to communicate about health questions and/or medication requests. Finally, 83% of user respondents were satisfied with the messaging system. Results highlight several areas where improvement is needed to increase patient use and satisfaction including adequate patient education, user-friendly interface, and provider engagement. No significant differences between the younger and older adult populations were found.

Conclusion: Although a majority of enrolled older adult patients have positive attitudes about health information exchange, electronic communication platforms must address key issues in consumer education, physician commitment, and adoption of an accessible interface to ensure productive older adult consumer participation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056337PMC
November 2013

Kinetics of oxidation of an organic amine with a Cr(V) salen complex in homogeneous aqueous solution and on the surface of mesoporous silica.

Dalton Trans 2009 May 9(17):3237-46. Epub 2009 Mar 9.

Ames Laboratory and Chemistry Department, Iowa State University, Ames, IA 50011, USA.

A comparative study of catalytic activity under homogeneous and heterogeneous conditions was carried out using the (salen)Cr(III)-catalyzed oxidation of tetramethylbenzidine (TMB) with iodosobenzene as a model reaction. Amine-functionalized mesoporous silica nanoparticles (MSN) were synthesized in a co-condensation reaction and functionalized with salen via a covalent Si-C bond. A Cr(III) complex of this supported ligand, MSN-(salen)Cr(III), was prepared and characterized. Data from powder XRD, BET isotherms and BJH pore size distribution all showed that MSN-(salen)Cr(III) still had the typical MSN high surface area, narrow pore size distribution, and ordered hexagonal pore structure, which were further confirmed by transmission electron microscopy (TEM) images. (13)C and (29)Si solid-state NMR data provided structural information about the catalyst and verified successful functionalization of the salen ligand and coordination to Cr(III). No unreacted salen or Cr(III) were observed. The loadings of salen and salen-Cr(III) complex were determined via TGA and EDX, respectively. Both measurements indicated that approximately 0.5 mmol/g of catalyst was loaded on the surface of MSN. The oxidation of TMB with iodosobenzene using MSN-(salen)Cr(III) as a heterogeneous catalyst exhibited both similarities and differences with the analogous homogeneous reaction using (salen)Cr(III)(H(2)O)(+) as a catalyst in aqueous acetonitrile. In the presence of 0.10 M HClO(4), the two catalytic reactions proceeded at similar rates and generated the doubly oxidized product TMB(2+). In the absence of acid, the radical cation TMB (+) was produced. The kinetics of the heterogeneous reaction in the absence of added acid responded to concentrations of all three reagents, i.e. (salen)Cr(III), TMB, and PhIO.
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http://dx.doi.org/10.1039/b900043gDOI Listing
May 2009

Endocytosis of a single mesoporous silica nanoparticle into a human lung cancer cell observed by differential interference contrast microscopy.

Anal Bioanal Chem 2008 Jul 17;391(6):2119-25. Epub 2008 May 17.

Ames Laboratory-USDOE and Department of Chemistry, Iowa State University, Ames, IA 50011, USA.

The unique structural features of mesoporous silica nanoparticles (MSN) have made them very useful in biological applications, such as gene therapy and drug delivery. Flow cytometry, confocal microscopy, and electron microscopy have been used for observing the endocytosis of MSN. However, flow cytometry cannot directly observe the process of endocytosis. Confocal microscopy requires fluorescence labeling of the cells. Electron microscopy can only utilize fixed cells. In the present work, we demonstrate for the first time that differential interference contrast (DIC) microscopy can be used to observe the entire endocytosis process of MSN into living human lung cancer cells (A549) without fluorescence staining. There are three physical observables that characterize the locations of MSN and the stages of the endocytosis process: motion, shape, and vertical position. When it was outside the cell, the MSN underwent significant Brownian motion in the cell growth medium. When it was trapped on the cell membrane, the motion of the MSN was greatly limited. After the MSN had entered the cell, it resumed motion at a much slower speed because the cytoplasm is more viscous than the cell growth medium and the cellular cytoskeleton networks act as obstacles. Moreover, there were shape changes around the MSN due to the formation of a vesicle after the MSN had been trapped on the cell membrane and prior to entry into the cell. Finally, by coupling a motorized vertical stage to the DIC microscope, we recorded the location of the MSN in three dimensions. Such accurate 3D particle tracking ability in living cells is essential for studies of selectively targeted drug delivery based on endocytosis.
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http://dx.doi.org/10.1007/s00216-008-2162-1DOI Listing
July 2008

Mesoporous silica nanomaterial-based biotechnological and biomedical delivery systems.

Nanomedicine (Lond) 2007 Feb;2(1):99-111

Department of Chemistry and US DOE Ames Laboratory, Iowa State University, Ames, IA 50011-3111, USA.

This review details the recent advancements in the design of mesoporous silica nanomaterials for controlled release drug, gene and neurotransmitter delivery applications. The high surface area (>900 m2/g), tunable pore diameter (2-20 nm) and uniform mesoporous structure (hexagonal channels or cubic pores) of the mesoporous silicas offer a unique advantage for loading and releasing large quantities of biomedical agents. Recent breakthroughs in controlling the particle size and shape of these materials have greatly improved the biocompatibility and the cellular uptake efficiency. The strategy of using various removable capping moieties, such as photo- or redox-responsive organic groups, inorganic nanoparticles, dendrimers and polymers, to encapsulate guest biomolecules inside the porous matrices further enables the utilization of these surface-functionalized mesoporous silica nanomaterials for stimuli-responsive controlled release in vitro and in vivo. In addition to the reviewed studies, many new and exciting applications of these novel materials will soon be realized.
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http://dx.doi.org/10.2217/17435889.2.1.99DOI Listing
February 2007

Tuning of particle morphology and pore properties in mesoporous silicas with multiple organic functional groups.

Chem Commun (Camb) 2003 Sep(18):2364-5

Department of Chemistry, Iowa State University, Ames, Iowa 50011-3111, USA.

A synthetic method has been developed that can control both multifunctionalization and morphology of the mesoporous organic-inorganic hybrid materials by introducing different molar ratios of organoalkoxysilane precursors to a base-catalyzed co-condensation of silicate.
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http://dx.doi.org/10.1039/b306255dDOI Listing
September 2003
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