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Article ; Online: Macrophage-derived CCL23 upregulates expression of T-cell exhaustion markers in ovarian cancer.

Kamat, Kalika / Krishnan, Venkatesh / Dorigo, Oliver

2022 Volume 127, Issue 6, Page(s) 1026–1033

Abstract: Background: Macrophages are an important component of the tumour immune microenvironment (TME) and can promote tumour growth and metastasis. Macrophage-secreted chemokine-ligand-23 (CCL23) induces ovarian cancer cell migration via chemokine-receptor 1 ( ... ...

Abstract	Background: Macrophages are an important component of the tumour immune microenvironment (TME) and can promote tumour growth and metastasis. Macrophage-secreted chemokine-ligand-23 (CCL23) induces ovarian cancer cell migration via chemokine-receptor 1 (CCR1). However, the effect of CCL23 on other immune cells in the TME is unknown. Methods: CCL23 levels were measured by ELISA. The expression of surface markers in exhaustion assays was quantified by flow cytometry. Signalling pathways were identified by phosphokinase array and validated by western blot. Results: Ascites from patients with high-grade serous ovarian cancer (HGSC) contain high levels of CCL23. Similarly, significantly higher CCL23 levels were found in plasma from HGSC patients compared to healthy individuals. RNA-seq analysis of ovarian cancer tissues from TCGA showed that expression of CCL23 correlated with the presence of macrophages. In tissues with high levels of CCL23 and macrophage content, the fraction of CD8 + T cells expressing exhaustion markers CTLA-4 and PD-1 were significantly higher compared to low-level CCL23 tissues. In vitro, CCL23 induced upregulation of immune checkpoint proteins on CD8 + T cells, including CTLA-4, TIGIT, TIM-3 and LAG-3 via phosphorylation of GSK3β in CD8 + T cells. Conclusions: Our data suggest that CCL23 produced by macrophages contributes to the immune-suppressive TME in ovarian cancer by inducing an exhausted T-cell phenotype.
MeSH term(s)	CTLA-4 Antigen ; Carcinoma, Ovarian Epithelial/metabolism ; Chemokine CCL22/metabolism ; Chemokines, CC/metabolism ; Female ; Humans ; Ligands ; Macrophages/metabolism ; Ovarian Neoplasms/metabolism ; Tumor Microenvironment
Chemical Substances	CCL23 protein, human ; CTLA-4 Antigen ; Chemokine CCL22 ; Chemokines, CC ; Ligands
Language	English
Publishing date	2022-06-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-022-01887-3
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Article ; Online: Challenges and Future Prospects of Targeting Myostatin/Activin A Signaling to Treat Diseases of Muscle Loss and Metabolic Dysfunction.

Lee, Se-Jin / Bhasin, Shalender / Klickstein, Lloyd / Krishnan, Venkatesh / Rooks, Daniel

The journals of gerontology. Series A, Biological sciences and medical sciences

2023 Volume 78, Issue Suppl 1, Page(s) 32–37

Abstract: Over the past 25 years, considerable progress has been made in terms of elucidating the regulatory and signaling mechanisms underlying the control of skeletal muscle mass by myostatin and other secreted proteins belonging to the transforming growth ... ...

Abstract	Over the past 25 years, considerable progress has been made in terms of elucidating the regulatory and signaling mechanisms underlying the control of skeletal muscle mass by myostatin and other secreted proteins belonging to the transforming growth factor-β superfamily. Preclinical studies demonstrating the potential benefits of targeting the activities of these ligands have fueled the development of numerous biologics capable of perturbing this signaling pathway and increasing muscle mass and function. These biologics have been tested in numerous clinical trials for a wide range of indications characterized by muscle loss and excess adiposity. Here, we review the results of these trials and discuss some of the challenges and future prospects for targeting this signaling pathway to treat muscle and metabolic diseases. Myostatin inhibitors may improve metabolic outcomes by increasing muscle mass, and metabolic disorders may be attractive potential indications for these molecules.
MeSH term(s)	Muscle, Skeletal/metabolism ; Myostatin ; Signal Transduction/physiology ; Transforming Growth Factor beta/metabolism
Chemical Substances	activin A ; Myostatin ; Transforming Growth Factor beta
Language	English
Publishing date	2023-02-06
Publishing country	United States
Document type	Review ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1223643-3
ISSN	1758-535X ; 1079-5006
ISSN (online)	1758-535X
ISSN	1079-5006
DOI	10.1093/gerona/glad033
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Article ; Online: Androgens and Selective Androgen Receptor Modulators to Treat Functional Limitations Associated With Aging and Chronic Disease.

Bhasin, Shalender / Krishnan, Venkatesh / Storer, Thomas W / Steiner, Mitchell / Dobs, Adrian S

The journals of gerontology. Series A, Biological sciences and medical sciences

2023 Volume 78, Issue Suppl 1, Page(s) 25–31

Abstract: Testosterone, many steroidal androgens, and nonsteroidal ligands that bind to androgen receptor and exert tissue-specific transcriptional activity (selective androgen receptor modulators [SARMs]) are being developed as function-promoting therapies to ... ...

Abstract	Testosterone, many steroidal androgens, and nonsteroidal ligands that bind to androgen receptor and exert tissue-specific transcriptional activity (selective androgen receptor modulators [SARMs]) are being developed as function-promoting therapies to treat functional limitations associated with aging and chronic diseases. This narrative review describes preclinical studies, mechanisms, and randomized trials of testosterone, other androgens, and nonsteroidal SARMs. Sex differences in muscle mass and strength and empiric use of anabolic steroids by athletes to increase muscularity and athletic performance provide supportive evidence of testosterone's anabolic effects. In randomized trials, testosterone treatment increases lean body mass, muscle strength, leg power, aerobic capacity, and self-reported mobility. These anabolic effects have been reported in healthy men, hypogonadal men, older men with mobility limitation and chronic diseases, menopausal women, and HIV-infected women with weight loss. Testosterone has not consistently improved walking speed. Testosterone treatment increases volumetric and areal bone mineral density, and estimated bone strength; improves sexual desire, erectile function, and sexual activity; modestly improves depressive symptoms; and corrects unexplained anemia in older men with low testosterone levels. Prior studies have not been of sufficient size or duration to determine testosterone's cardiovascular and prostate safety. The efficacy of testosterone in reducing physical limitations, fractures, falls, progression to diabetes, and correcting late-onset persistent depressive disorder remains to be established. Strategies to translate androgen-induced muscle mass and strength gains into functional improvements are needed. Future studies should evaluate the efficacy of combined administration of testosterone (or a SARM) plus multidimensional functional exercise to induce neuromuscular adaptations required for meaningful functional improvements.
MeSH term(s)	Humans ; Female ; Male ; Aged ; Androgens ; Receptors, Androgen/metabolism ; Anabolic Agents/adverse effects ; Testosterone/therapeutic use ; Androgen Antagonists/therapeutic use ; Chronic Disease ; Aging
Chemical Substances	Androgens ; Receptors, Androgen ; Anabolic Agents ; Testosterone (3XMK78S47O) ; Androgen Antagonists
Language	English
Publishing date	2023-06-16
Publishing country	United States
Document type	Review ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1223643-3
ISSN	1758-535X ; 1079-5006
ISSN (online)	1758-535X
ISSN	1079-5006
DOI	10.1093/gerona/glad027
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Article ; Online: Immune health grades: Finding resilience in the COVID-19 pandemic and beyond.

Marconi, Vincent C / Krishnan, Venkatesh / Ely, E Wesley / Montano, Monty

The Journal of allergy and clinical immunology

2021 Volume 149, Issue 2, Page(s) 565–568

MeSH term(s)	COVID-19 ; Humans ; Pandemics ; SARS-CoV-2
Language	English
Publishing date	2021-11-02
Publishing country	United States
Document type	Editorial ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2021.10.025
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Article ; Online: Comparison of pullout strength of pedicle screws following revision using larger diameter screws.

Varghese, Vicky / Krishnan, Venkatesh / Kumar, Gurunathan Saravana

Medical engineering & physics

2019 Volume 74, Page(s) 180–185

Abstract: Pedicle screw fixation and fusion are the gold standard for the treatment of spinal instability. Screw failures such as pullout and breakages have been reported during the past several years of research and development in this field. Further, the rate of ...

Abstract	Pedicle screw fixation and fusion are the gold standard for the treatment of spinal instability. Screw failures such as pullout and breakages have been reported during the past several years of research and development in this field. Further, the rate of revision surgeries due to failed pedicle screws is around 2-12%. This creates unavoidable hardship to the patients. Improper screw size for revision surgery can lead to complications such as pedicle fractures, screw pullout, or reduced stability of the fusion construct. We performed pullout strength studies on five osteoporotic lumbar vertebra and a rigid polyurethane foam block to find the effect of the outer diameter of revision screws as per American Standards for Testing of Materials (ASTM) 543-07 protocol. The present study revealed that whereas the use of revision screws that were one millimeter greater in diameter than the original screws decreased the pullout strength by 79% in the foam model, the pullout strength increased by 121% when the original index screws were replaced with screws that were two millimeters greater in diameter. The effect of revision screw diameter on pullout strength was significant (p < 0.05). Cadaveric testing reveals a trend that agrees with the foam model tests.
MeSH term(s)	Cadaver ; Humans ; Mechanical Phenomena ; Pedicle Screws ; Reoperation
Language	English
Publishing date	2019-09-19
Publishing country	England
Document type	Comparative Study ; Journal Article
ZDB-ID	1181080-4
ISSN	1873-4030 ; 1350-4533
ISSN (online)	1873-4030
ISSN	1350-4533
DOI	10.1016/j.medengphy.2019.09.008
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Article: Exploring the Effects of Ixekizumab on Pain in Patients with Ankylosing Spondylitis Based on Objective Measures of Inflammation: Post Hoc Analysis from a Large Randomized Clinical Trial.

de Vlam, Kurt / Maksymowych, Walter P / Gallo, Gaia / Rahman, Proton / Mease, Philip / Krishnan, Venkatesh / McVeigh, Conor J / Lisse, Jeffrey / Zhu, Danting / Bolce, Rebecca J / Conaghan, Philip G

Rheumatology and therapy

2024

Abstract: Introduction: The objective of this analysis is to evaluate the improvement in spinal pain with ixekizumab, placebo, and adalimumab based on objective measures of inflammation response in patients with ankylosing spondylitis (AS).: Methods: The COAST- ...

Abstract	Introduction: The objective of this analysis is to evaluate the improvement in spinal pain with ixekizumab, placebo, and adalimumab based on objective measures of inflammation response in patients with ankylosing spondylitis (AS). Methods: The COAST-V 52-week, double-blind, placebo-controlled, randomized phase III trial examined the efficacy of ixekizumab in patients with active AS; adalimumab was used as an active reference arm. Treatment effects on reduction in pain were assessed by objective measures of controlled and persisting inflammation (defined by magnetic resonance imaging [MRI], C-reactive protein [CRP], or MRI + CRP status). Pathway analysis was used to analyze treatment effect that was not attributable to reduction in inflammation biomarkers. Results: In patients with AS, when inflammation was controlled as assessed by MRI, patients treated with ixekizumab experienced a reduction in spinal pain at night (SP-N, numeric rating scale, ixekizumab mean = - 3.9, p < 0.001, adalimumab mean = - 2.6, p < 0.05) compared to placebo (mean = - 1.6) at week 16. When inflammation was controlled as assessed by MRI + CRP, ixekizumab and adalimumab had numerically greater reductions at week 16 in SP-N versus placebo. All ixekizumab groups had further improvements at week 52. When inflammation was persisting as assessed by MRI + CRP, ixekizumab-treated patients had significant reduction in SP-N (mean = - 3.7, p < 0.001) versus placebo (mean = - 1.7), improvement with adalimumab did not reach significance (mean = - 2.6, p = 0.06). In the pathway analysis at week 16, ixekizumab had a greater effect on pain outcomes compared to adalimumab. Conclusion: This post hoc analysis is supportive of the hypothesis that ixekizumab reduces pain in AS by additional mechanisms other than the reduction of measurable inflammation. Trial registration number: NCT02696785.
Language	English
Publishing date	2024-04-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2783278-8
ISSN	2198-6584 ; 2198-6576
ISSN (online)	2198-6584
ISSN	2198-6576
DOI	10.1007/s40744-024-00660-7
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Article ; Online: Cell-based immunotherapy in gynecologic malignancies.

Kamat, Kalika / Krishnan, Venkatesh / Berek, Jonathan S / Dorigo, Oliver

Current opinion in obstetrics & gynecology

2020 Volume 33, Issue 1, Page(s) 13–18

Abstract: Purpose of review: To provide an update on cell-based immunotherapies in solid tumors particularly in gynecological cancers.: Recent findings: Recent clinical trial results demonstrate safety and tolerability of different cell therapies in ... ...

Abstract	Purpose of review: To provide an update on cell-based immunotherapies in solid tumors particularly in gynecological cancers. Recent findings: Recent clinical trial results demonstrate safety and tolerability of different cell therapies in gynecological cancers. Novel approaches, such as harnessing the cells of the innate immune system are also under investigation in a phase I trial. Summary: Cell-based therapies are gaining widespread attention as evidenced by the increasing number of clinical trials encompassing both, innate and adaptive cells to target gynecological cancers. A majority of these therapeutic approaches are well tolerated and show promising results in early trials.
MeSH term(s)	Cell- and Tissue-Based Therapy ; Female ; Genital Neoplasms, Female/therapy ; Humans ; Immunotherapy
Language	English
Publishing date	2020-12-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1049382-7
ISSN	1473-656X ; 1040-872X
ISSN (online)	1473-656X
ISSN	1040-872X
DOI	10.1097/GCO.0000000000000676
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Article: Does the Surgical Reduction of High Grade Spondylolisthesis Restore Spino-Pelvic Alignment? An Analysis of 35 Patients.

Amritanand, Rohit / Arockiaraj, Justin / David, Kenny S / Krishnan, Venkatesh

Asian spine journal

2020 Volume 15, Issue 5, Page(s) 596–603

Abstract: Study design: Retrospective case series.: Purpose: This study aimed to analyze how the sagittal spinopelvic alignment is influenced by an attempted surgical reduction of the L5-S1 segment in patients with high-grade spondylolisthesis (HGS).: ... ...

Abstract	Study design: Retrospective case series. Purpose: This study aimed to analyze how the sagittal spinopelvic alignment is influenced by an attempted surgical reduction of the L5-S1 segment in patients with high-grade spondylolisthesis (HGS). Overview of literature: Conventional treatment strategies stress the importance of achieving fusion across the lumbosacral junction in patients with HGS. The role of reduction in this subset of patients is controversial. Methods: This is a retrospective case series of 35 patients with Meyerding grades III, IV, or V spondylolisthesis who underwent surgical treatment in our institution. Before and after surgery, we took standing lateral radiographs from L1 vertebra to pelvis, including the femoral heads, and measured the slip grade, pelvic incidence, sacral slope, pelvic tilt, lumbosacral angle, and lumbar lordosis. Patients were subdivided into "balanced" and "unbalanced" pelvis groups. To determine the effect and correlation of reduction on these spinopelvic parameters, we statistically compared the pre- and postoperative measurements. Results: The average follow-up was 9 months (range, 3-169 months). Slip grade improved from an average 74.0%±13.2% to 30.0%±14.0% (p<0.001), and lumbosacral angle reduced from an average 32.0°±11.6° to 6.0°±0.6° (p<0.001). Although the pelvic tilt was reduced, this was not significant. There was a modest negative correlation between the reduction in slip grade and the increase in sacral slope (r=-0.3, p=0.06). At follow-up, five patients improved, from an unbalanced pelvis to a balanced pelvis. Fusion occurred in 33 patients (95%). Conclusions: Surgical reduction of HGS restores the lumbosacral alignment. However, a similar trend is not noted with the pelvic parameters.
Language	English
Publishing date	2020-11-16
Publishing country	Korea (South)
Document type	Journal Article
ZDB-ID	2559763-2
ISSN	1976-7846 ; 1976-1902
ISSN (online)	1976-7846
ISSN	1976-1902
DOI	10.31616/asj.2020.0252
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Zs.A 6861: Show issues

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Article: Identification of Pedicle Screw Pullout Load Paths for Osteoporotic Vertebrae.

Krishnan, Venkatesh / Varghese, Vicky / Kumar, Gurunathan Saravana / Yoganandan, Narayan

Asian spine journal

2020 Volume 14, Issue 3, Page(s) 273–279

Abstract: Study design: A biomechanical study.: Purpose: To determine the actual load path and compare pullout strengths as a function of screw size used in revision surgeries using postmortem human subject specimens.: Overview of literature: Pedicle screw ... ...

Abstract	Study design: A biomechanical study. Purpose: To determine the actual load path and compare pullout strengths as a function of screw size used in revision surgeries using postmortem human subject specimens. Overview of literature: Pedicle screw fixation has become the standard of care in the surgical management of spinal instability. However, pullout failures are widely observed in osteoporotic spines and treated by revision surgeries using a higher diameter screw, performing cement augmentation, or increasing the levels of fixation. While the peak forces to final pullout are reported, the actual load path to achieve the final force level is not available. Methods: Six osteoporotic lumbar spines (L2-L5) were instrumented with 5.5×40 mm polyaxial screws and loaded along the axis of the screw using a material testing machine according to American Society for Testing of Materials 543-07 test protocol. Tests were again conducted by replacing them with 6.5×40 mm (group A) or 7.5×40 mm (group B) screws. Force-displacement data were grouped and load paths (mean±1 standard deviation) were compared. Results: Pullout strength decreased by 36% when the size of the revision screw was increased by 1 mm, while it increased by 35% when the size of the revision screw was increased by 2 mm compared to the index screw value. While the morphologies of the load paths were similar in all cases, they differ between the two groups: the larger screw responded with generally elevated stiffer path than the smaller screw, suggesting that revision surgery using a larger screw has more purchase along the inserted body-pedicle axis. Conclusions: A larger screw enhances strength and increases biomechanical stability in revision surgeries, although the final surgical decision is made by the clinician, which includes the patient's anatomy and associated characteristics.
Language	English
Publishing date	2020-01-17
Publishing country	Korea (South)
Document type	Journal Article
ZDB-ID	2559763-2
ISSN	1976-7846 ; 1976-1902
ISSN (online)	1976-7846
ISSN	1976-1902
DOI	10.31616/asj.2019.0174
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Article ; Online: Cell-based immunotherapy in gynecologic malignancies.

Schaar, Bruce / Krishnan, Venkatesh / Tallapragada, Supreeti / Dorigo, Oliver

Current opinion in obstetrics & gynecology

2018 Volume 30, Issue 1, Page(s) 23–30

Abstract: Purpose of review: To provide an overview of the principles, safety and efficacy of adoptive cell therapy (ACT) in solid tumors particularly in gynecological cancers.: Recent findings: Efforts to target solid tumors using tumor-infiltrating ... ...

Abstract	Purpose of review: To provide an overview of the principles, safety and efficacy of adoptive cell therapy (ACT) in solid tumors particularly in gynecological cancers. Recent findings: Efforts to target solid tumors using tumor-infiltrating lymphocytes and genetically modified T cells have shown promising efficacy in some patients. Two food and drug administration approvals for the treatment of leukemia are the first gene therapies available for cancer treatment in the United States. Summary: Genetic engineering of antitumor immunity using T cells has the potential to target specific tumor-associated antigens and overcome obstacles to successful immunotherapy like immune-suppressive factors in the tumor microenvironment.
MeSH term(s)	Antineoplastic Agents, Immunological/adverse effects ; Antineoplastic Agents, Immunological/therapeutic use ; Female ; Genetic Engineering ; Genetic Therapy/trends ; Genital Neoplasms, Female/genetics ; Genital Neoplasms, Female/immunology ; Genital Neoplasms, Female/metabolism ; Genital Neoplasms, Female/therapy ; Humans ; Immunotherapy, Adoptive/adverse effects ; Immunotherapy, Adoptive/trends ; Models, Immunological ; Molecular Targeted Therapy/adverse effects ; Molecular Targeted Therapy/trends ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/transplantation ; United States ; United States Food and Drug Administration
Chemical Substances	Antineoplastic Agents, Immunological
Language	English
Publishing date	2018-02
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1049382-7
ISSN	1473-656X ; 1040-872X
ISSN (online)	1473-656X
ISSN	1040-872X
DOI	10.1097/GCO.0000000000000433
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