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Article: Long-lasting cigarette smoking alterations in immune function occur in cannabis smokers, possibly rendering them vulnerable to smoking-related tumors in later life.

Lehrer, Steven / Rheinstein, Peter H

medRxiv : the preprint server for health sciences

2024

Abstract: Background: Active cigarette smoking leads to increased CXCL5 production. CXCL5 mediates the immune response by attracting immune cells to areas of inflammation. Elevated CXCL5 levels are associated with various inflammatory diseases and tumorigenesis. ... ...

Abstract	Background: Active cigarette smoking leads to increased CXCL5 production. CXCL5 mediates the immune response by attracting immune cells to areas of inflammation. Elevated CXCL5 levels are associated with various inflammatory diseases and tumorigenesis. In addition, smoking is linked to an increase in the level of the cytokine CEACAM6 in the bloodstream of smokers. CEACAM6 is increased in pancreatic adenocarcinoma, breast cancer, non small cell lung cancer, gastric cancer, colon cancer and other cancers and promotes tumor progression, invasion, and metastasis. Although cytokine secretion in the innate immune response returns to nonsmoker levels after quitting smoking, the effects on the adaptive response appear to persist for years or decades due to epigenetic memory. As a result, epigenetic changes induced by smoking may contribute to long-lasting alterations in immune function, including elevated CXCL5 and CEACAM6. The effects of cannabis smoking might be similar. Methods: In the current study we used UK Biobank (UKB) data to assess the relationship of CXCL5, CEACAM6, and pulmonary function to cigarette and cannabis smoking. Our UK Biobank application was approved as UKB project 57245 (S.L., P.H.R.). Our analysis included all subjects with smoking and/or marijuana use data in the UK Biobank database. Circulating levels of CXCL5 and CEACAM6 were from UKB Olink data. Individual CXCL5 and CEACAM6 levels are NPX, Normalized Protein expression, Olink arbitrary unit in Log2 scale (Olink Proteomics AB, Uppsala, Sweden; http://www.olink.com). Results: Current smokers and past smokers had elevated circulating levels of CXCL5 and CECAM6. In multivariate analysis, current, past, or no smoking history was significantly related to CXCL5 level and CECAM6 levels, independent of the effects of age, sex. Frequency of cannabis use had a similar effect. In multivariate analysis, frequency of cannabis use was significantly related to CXCL5 level and CECAM6 levels, independent of the effects of age, sex, and years between last cannabis use and enrollment in study. Conclusion: we can confirm a previous report of epigenetic changes induced by cigarette smoking that may contribute to long-lasting alterations in immune function related to CXCL5 and CEACAM6. In addition, we have found that these same long-lasting smoking alterations in immune function related to CXCL5 and CEACAM6 occur in cannabis smokers, possibly rendering them vulnerable to smoking-related tumors in later life.
Language	English
Publishing date	2024-04-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.01.24305156
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Article ; Online: Alignment of human aquaporin 4 and ß-amyloid proteins may indicate involvement of ß-amyloid in brain water homeostasis and prevention of brain edema.

Lehrer, Steven / Rheinstein, Peter H

Chronic diseases and translational medicine

2023 Volume 9, Issue 2, Page(s) 177–181

Language	English
Publishing date	2023-03-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2831148-6
ISSN	2589-0514 ; 2589-0514
ISSN (online)	2589-0514
ISSN	2589-0514
DOI	10.1002/cdt3.64
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Increased survival of women with luminal breast cancer and progesterone receptor immunohistochemical expression of greater than 10.

Lehrer, Steven / Rheinstein, Peter H

Cancer

2023 Volume 129, Issue 13, Page(s) 2103–2104

MeSH term(s)	Female ; Humans ; Breast Neoplasms ; Receptors, Progesterone/metabolism ; Progesterone ; Receptor, ErbB-2/metabolism ; Biomarkers, Tumor/metabolism
Chemical Substances	Receptors, Progesterone ; Progesterone (4G7DS2Q64Y) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Biomarkers, Tumor
Language	English
Publishing date	2023-04-27
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	1429-1
ISSN	1097-0142 ; 0008-543X ; 1934-662X
ISSN (online)	1097-0142
ISSN	0008-543X ; 1934-662X
DOI	10.1002/cncr.34828
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Article ; Online: Inhaled biguanides and mTOR inhibition for influenza and coronavirus (Review).

Lehrer, Steven

World Academy of Sciences journal

2020 Volume 2, Issue 3

Abstract: The mammalian target of rapamycin (mTOR) signaling pathway senses and responds to nutrient availability, energy sufficiency, stress, hormones and mitogens to modulate protein synthesis. Rapamycin is a bacterial product that can inhibit mTOR via the PI3K/ ... ...

Abstract	The mammalian target of rapamycin (mTOR) signaling pathway senses and responds to nutrient availability, energy sufficiency, stress, hormones and mitogens to modulate protein synthesis. Rapamycin is a bacterial product that can inhibit mTOR via the PI3K/AKT/mTOR pathway. mTOR signaling is necessary for the development of influenza and modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. In one human study, it was found that the treatment of severe H1N1 influenza‑related pneumonia with rapamycin and steroids improved the outcome. However, in other studies, immunosuppression with systemic steroids, and possibly rapamycin as well, was associated with an increased morbidity/mortality and a prolonged viral replication. In order to avoid the systemic side-effects, some investigators have postulated that the inhalation of rapamycin would be desirable. However, the inhalation of rapamycin, with its well-documented lung toxicity, could be contraindicated. Another class of drug, biguanides, can also inhibit mTOR, but have no lung toxicity. Biguanides are widely used small molecule drugs prescribed as oral anti-diabetics that have exhibited considerable promise in oncology. During the 1971 outbreak of influenza, diabetic patients treated with the biguanides, phenformin and buformin, had a lower incidence of infection than diabetics treated with sulfonylureas or insulin. Both buformin and phenformin reduce the mortality of influenza in mice; phenformin is less effective than buformin. The inhalation of buformin or phenformin for influenza may be an effective novel treatment strategy that would limit the risk of systemic side-effects associated with biguanides due to the low inhaled dose. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2, a virus closely related to the SARS virus. The disease is the cause of the 2019-2020 coronavirus outbreak. It is primarily spread between individuals via small droplets emitted from infected individuals when breathing or coughing. PI3K/AKT/mTOR signaling responses play important roles in MERS-CoV infection and may represent a novel drug target for therapeutic intervention strategies. The present review article discusses the effects of biguanides on influenza and coronavirus.
Keywords	covid19
Language	English
Publishing date	2020-03-29
Publishing country	England
Document type	Journal Article
ISSN	2632-2919
ISSN (online)	2632-2919
DOI	10.3892/wasj.2020.42
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Article ; Online: Predicted Configuration and Stability of the ATAD2/SOX10 Complex Using Molecular Dynamics Simulations.

Lehrer, Steven / Rheinstein, Peter H

Cancer diagnosis & prognosis

2023 Volume 3, Issue 3, Page(s) 398–402

Abstract: Background/aim: ATAD2, a melanoma competence factor, forms a protein complex with SOX10 that facilitates expression of SOX10 developmental target genes. The complex enables a strong transcriptional response to oncogenes such as BRAF: Materials and ... ...

Abstract	Background/aim: ATAD2, a melanoma competence factor, forms a protein complex with SOX10 that facilitates expression of SOX10 developmental target genes. The complex enables a strong transcriptional response to oncogenes such as BRAF Materials and methods: We used the ClusPro web server for protein-protein docking to visualize and analyze the complex and GROMACS to perform molecular dynamics simulations. Results: ClusPro protein docking analysis demonstrated the central position of ADAT2 in the ADAT2/SOX10 complex. Molecular dynamics simulations of ATAD2 docked to SOX10 suggest that ATAD2/SOX10 is not a stable structure. Conclusion: The central position of ADAT2 in the complex suggested that ADAT2 complexed to SOX10 may have the capability to modify multiple functions of the latter, one of which allows BRAF
Language	English
Publishing date	2023-05-03
Publishing country	Greece
Document type	Journal Article
ISSN	2732-7787
ISSN (online)	2732-7787
DOI	10.21873/cdp.10231
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Article ; Online: Re: Suppressing c-FOS expression by G-quadruplex ligands inhibits osimertinib-resistant non-small cell lung cancers.

Lehrer, Steven / Rheinstein, Peter H

Journal of the National Cancer Institute

2023 Volume 115, Issue 11, Page(s) 1427–1428

MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Acrylamides/pharmacology ; Acrylamides/therapeutic use ; Aniline Compounds/pharmacology ; Aniline Compounds/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Mutation ; Drug Resistance, Neoplasm/genetics ; Cell Line, Tumor
Chemical Substances	osimertinib (3C06JJ0Z2O) ; Acrylamides ; Aniline Compounds ; Protein Kinase Inhibitors
Language	English
Publishing date	2023-08-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djad167
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Article ; Online: Increased KCNN4 Expression Is Correlated With Poor Survival in Lower Grade Glioma.

Lehrer, Steven / Rheinstein, Peter H

Cancer diagnosis & prognosis

2023 Volume 3, Issue 4, Page(s) 428–432

Abstract: Background/aim: Networks of glioma cells are linked to small groups of pacemaker cells in which levels of calcium ions pulse periodically, driving a signal through the network that causes tumor growth. Using inhibitors, one study blocked the activity of ...

Abstract	Background/aim: Networks of glioma cells are linked to small groups of pacemaker cells in which levels of calcium ions pulse periodically, driving a signal through the network that causes tumor growth. Using inhibitors, one study blocked the activity of the Ca Materials and methods: KCa3.1 is encoded by the gene potassium calcium-activated channel subfamily N member 4 (KCNN4) on the chromosomal location 19q13.31. We used the Cancer Genome Atlas (TCGA) to evaluate the effect of KCNN4 on human glioma survival in the TCGA Lower Grade Glioma (LGG) dataset. Results: In humans, KCNN4 is prognostic in glioma; high expression is unfavorable. In addition, KCNN4 copy number variations are prognostic. Increased masked copy number segments are unfavorable in lower grade glioma. KCNN4 is lost in gliomas with the 1p 19q co-deletion, which may explain in part the comparatively favorable prognosis of 1p 19q co-deletion tumors. Conclusion: Our finding of increased KCNN4 expression related to poor survival in human lower grade glioma suggests that developing novel therapies, such as KCa3.1-inhibiting drugs, might be worthwhile.
Language	English
Publishing date	2023-07-03
Publishing country	Greece
Document type	Journal Article
ISSN	2732-7787
ISSN (online)	2732-7787
DOI	10.21873/cdp.10235
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Article: Chromosome 1p deletion in colorectal cancer and lower grade glioma: possible relationship with the enteric nervous system.

Lehrer, Steven / Rheinstein, Peter H

medRxiv : the preprint server for health sciences

2023

Abstract: Background: Enteric neurons and enteric glial cells are a part of the enteric nervous system, which is sometimes referred to as the "second brain" of the body. This complex network of neurons controls various functions of the gastrointestinal tract, ... ...

Abstract	Background: Enteric neurons and enteric glial cells are a part of the enteric nervous system, which is sometimes referred to as the "second brain" of the body. This complex network of neurons controls various functions of the gastrointestinal tract, including motility, secretion, and blood flow. Research has shown that there is a connection between enteric neurons and the development of colorectal cancer, although the exact mechanisms are still being studied. Methods: Because of the potential influence of chromosome mutations that may be common to both gliomas and colorectal cancer, we used the Cancer Genome Atlas (TCGA) to examine these mutations. Results: 166 of 506 lower grade gliomas had the 1p 19q co-deletion. 150 of 616 colorectal cancers had a 1p deletion but no 19q deletion. Conclusion: Colorectal cancer cells adhere to and migrate along the neurons of the enteric nervous system. Therefore, cancer cells might be expected to pick up mutations from neurons and enteric glial cells during recombination events. We hypothesize that the chromosome 1p deletion in colorectal cancer above is not a chance event and instead was acquired from adjacent enteric glial cells. Chromosome 1p co-deletion may confer better survival in patients with lower grade glioma in part because of loss of the MycBP oncogene, which is important in glioma development. Enteric glia might have the chromosome 1p deletion but lack the chromosome 19q deletion of CNS gliomas, making them much less vulnerable to malignant transformation than CNS gliomas. Indeed, evidence exists for a tumor suppressor gene on chromosome 19q associated with human astrocytomas, oligodendrogliomas, and mixed gliomas.
Language	English
Publishing date	2023-12-22
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.07.23298214
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Article ; Online: Increased Maternal Compared to Paternal Transmission of Alzheimer's Disease May Be Due to Increased Incidence of Depression in Women.

Lehrer, Steven / Rheinstein, Peter H

In vivo (Athens, Greece)

2023 Volume 37, Issue 6, Page(s) 2447–2451

Abstract: Background: Mothers transmit Alzheimer's disease (AD) more frequently than fathers. Factors other than female longevity may be at work to promote maternal transmission of AD. Among these are the X chromosome, mitochondrial DNA, and AD comorbidities, ... ...

Abstract	Background: Mothers transmit Alzheimer's disease (AD) more frequently than fathers. Factors other than female longevity may be at work to promote maternal transmission of AD. Among these are the X chromosome, mitochondrial DNA, and AD comorbidities, especially depression. A recent study associated mitochondrial SNP rs2853499 with AD. Materials and methods: We used UK Biobank (UKBB) data to investigate the relation of mitochondrial SNP rs2853499, with AD. To identify cases of AD we used ICD10 code G30.9. Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai. We used PLINK, a whole-genome association analysis toolset, to analyze the UKB22418 mitochondrial hard-called chromosome file. Results: Of 953 AD cases, 493 were male (51.7%) and 460 were female (48.3%). Mothers were twice as likely to transmit AD compared to fathers. We found that in individuals with AD, 22.3% (n=201) carried the A allele of SNP rs2853499, 77.7% (n=700) carried the G allele. In individuals without AD, 22.2% (n=10,7726) carried the A allele of SNP rs2853499, 77.8% (n=378,535) carried the G allele. This difference was not significant (p=0.91, two-tailed Fisher exact test). Therefore, factors other than mitochondrial SNP rs2853499 may be at work to promote maternal transmission of AD. Conclusion: We conclude that depression, a multigenic illness, in the mother is most likely the basis for the fact that mothers transmit AD twice as often as fathers.
MeSH term(s)	Humans ; Male ; Female ; Alzheimer Disease/epidemiology ; Alzheimer Disease/genetics ; Depression/epidemiology ; Depression/genetics ; Incidence ; Fathers ; Mothers ; DNA, Mitochondrial
Chemical Substances	DNA, Mitochondrial
Language	English
Publishing date	2023-11-01
Publishing country	Greece
Document type	Journal Article
ZDB-ID	807031-3
ISSN	1791-7549 ; 0258-851X
ISSN (online)	1791-7549
ISSN	0258-851X
DOI	10.21873/invivo.13350
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Article ; Online: Insulin Docking Within the Open Hemichannel of Connexin 43 May Reduce Risk of Amyotrophic Lateral Sclerosis.

Lehrer, Steven / Rheinstein, Peter H

In vivo (Athens, Greece)

2023 Volume 37, Issue 2, Page(s) 539–547

Abstract: Background/aim: Type 2 diabetes (T2D), characterized by hyperinsulinemia, protects motor neurons against amyotrophic lateral sclerosis (ALS). Type 1 diabetes and a total lack of insulin are associated with increased risk of ALS. Connexin 43 (Cx43), an ... ...

Abstract	Background/aim: Type 2 diabetes (T2D), characterized by hyperinsulinemia, protects motor neurons against amyotrophic lateral sclerosis (ALS). Type 1 diabetes and a total lack of insulin are associated with increased risk of ALS. Connexin 43 (Cx43), an astrocyte protein, operates as an open pore via which toxic substances from the astrocytes reach motor neurons. Materials and methods: In the current study, we performed molecular docking of insulin with monomeric Cx31, monomeric Cx43, and hexameric Cx31 to assess whether insulin might affect the pore. Hexameric Cx31 and hexameric Cx43 are transmembrane hemichannels composed of 6 subunits; they bind together to form gap junction intercellular channels. We used the program AutoDock Vina Extended for the molecular docking study. Results: Cx31 shares amino acid and structural similarity to Cx43, and insulin docks to the same position at the N-terminal domain of monomeric Cx31 and monomeric Cx43. Insulin docks within the open hemichannel of hexameric Cx31, potentially blocking it. Molecular dynamics simulation shows that the block is highly stable and may be responsible for the protective effect of T2D on ALS. Conclusion: Insulin, especially intranasal insulin, might be a treatment for ALS. An insulin secretogogue such as oral sulfonylurea or meglitinide might also be of value.
MeSH term(s)	Humans ; Insulin ; Amyotrophic Lateral Sclerosis/drug therapy ; Connexin 43 ; Diabetes Mellitus, Type 2 ; Molecular Docking Simulation
Chemical Substances	Insulin ; Connexin 43
Language	English
Publishing date	2023-03-07
Publishing country	Greece
Document type	Journal Article
ZDB-ID	807031-3
ISSN	1791-7549 ; 0258-851X
ISSN (online)	1791-7549
ISSN	0258-851X
DOI	10.21873/invivo.13112
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