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One-carbon metabolism and breast cancer: an epidemiological perspective

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Journal of Genetics and Genomics 2009年第4期36卷 203-214页

作者： Xinran Xu Jia Chen Department of Community and Preventive medicine Mount Sinai School of Medicine New York NY10029 USA Department of Pediatrics Mount Sinai School of Medicine New York NY 10029 USA Department of Oncological Science Mount Sinai School of Medicine New York iVY 10029 USA

One-carbon metabolism is a network of biological reactions that plays critical role in DNA methylation and DNA synthesis, and in turn, facilitates the cross-talk between genetic and epigenetic processes. Genetic polymorphisms and supplies of cofactors （e.g. folate, vitamins B） involved in this pathway have been shown to influence cancer risk and even survival. In this review, we summarized the epidemiological evidence for one-carbon metabolism, from both genetics and lifestyle aspects, in relation to breast cancer risk. We also discussed this pathway in relation to breast cancer survival and the modulation of one-carbon polymorphism in chemotherapy. Emerging evidence on modulation of DNA methylation by one-carbon metabolism suggests that disruption of epigenome might have been the underlying mechanism. More results are expected and will be translated to guidance to the general population for disease prevention as well as to clinicians for treatment and management of the disease.

关键词： one-carbon breast cancer folate genetic polymorphism DNA methylation epidemiology

Personalized medicine in non-small cell lung cancer: a review from a pharmacogenomics perspective

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Acta Pharmaceutica Sinica B 2018年第4期8卷 530-538页

作者： Wenxiao Jiang Guiqing Cai Peter C.Hu Yue Wang Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai The University of Texas MD Anderson Cancer Center Department of Molecular and Human Genetics Baylor College of Medicine

Non-small cell lung cancer is a prevalent and rapidly-expanding challenge to modern medicine. While generalized medicine with traditional chemotherapy yielded comparatively poor response rates and treatment results, the cornerstone of personalized medicine using genetic profiling to direct treatment has exalted the successes seen in the field and raised the standard for patient treatment in lung and other cancers. Here, we discuss the current state and advances in the field of personalized medicine for lung cancer, reviewing several of the mutation-targeting strategies that are approved for clinical use and how they are guided by patient genetic information. These classes include inhibitors of tyrosine kinase(TKI), anaplastic lymphoma kinase(ALK), and monoclonal antibodies. Selecting from these treatment plans and determining the optimal dosage requires in-depth genetic guidance with consideration towards not only the underlying target genes but also other factors such as individual metabolic capability and presence of resistance-conferring mutations both directly on the target gene and along its cascade(s).Finally, we provide our viewpoints on the future of personalized medicine in lung cancer, including target-based drug combination, mutation-guided drug design and the necessity for data of population genetics, to provide rough guidance on treating patients who are unable to get genetic testing.

关键词： Personalized medicine Non-small cell lung cancer Pharmacogenomics Tyrosine kinase Anaplastic lymphoma kinase Inhibitor Monoclonal antibody

Minimally invasive procedures on the lumbar spine

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World Journal of Clinical Cases 2015年第1期3卷 1-9页

作者： Branko Skovrlj Jeffrey Gilligan Holt S Cutler Sheeraz A Qureshi Department of Neurosurgery Icahn School of Medicine at Mount Sinai New York NY 10029 United States Albert Einstein College of medicine of Yeshiva University Bronx NY 10461 United States Department of Orthopaedics Icahn School of Medicine at Mount Sinai New York NY 10029 United States

Degenerative disease of the lumbar spine is a common and increasingly prevalent condition that is often implicated as the primary reason for chronic low back pain and the leading cause of disability in the western world. Surgical management of lumbar degenerative disease has historically been approached by way of open surgical procedures aimed at decompressing and/or stabilizing the lumbar spine. Advances in technology andsurgical instrumentation have led to minimally invasive surgical techniques being developed and increasingly used in the treatment of lumbar degenerative disease. Compared to the traditional open spine surgery, minimally invasive techniques require smaller incisions and decrease approach-related morbidity by avoiding muscle crush injury by self-retaining retractors, preventing the disruption of tendon attachment sites of important muscles at the spinous processes, using known anatomic neurovascular and muscle planes, and minimizing collateral soft-tissue injury by limiting the width of the surgical corridor. The theoretical benefits of minimally invasive surgery over traditional open surgery include reduced blood loss, decreased postoperative pain and narcotics use, shorter hospital length of stay, faster recover and quicker return to work and normal activity. This paper describes the different minimally invasive techniques that are currently available for the treatment of degenerative disease of the lumbar spine.

关键词： Minimally invasive surgery Spine surgery Lumbar spine Degenerative disease Interbody fusion Posterolateral fusion Decompression Indirect decompression techniques

NUMB maintains bone mass by promoting degradation of PTEN and GLI1 via ubiquitination in osteoblasts

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Bone Research 2018年第4期6卷 368-382页

作者： Ling Ye Feng Lou Fanyuan Yu Demao Zhang Chenglin Wang Fanzi Wu Xin Li Yilin Ping Xiao Yang Jing Yang Dian Chen Bo Gao Dingming Huang Peng Liu State Key Laboratory of Oral Disease West China Hospital of Stomatology Sichuan University The mount sinai Bone Program Department of MedicineMount Sinai School of Medicine

The adaptor protein NUMB is involved in asymmetric division and cell fate determination and recognized as an antagonist of *** studies have proved that Notch activation in osteoblasts contributes to a high bone mass. In this study, however, an osteopenic phenotype was found in 9-week-old mice using osteoblastic specific Col1a1–2.3-Cre to ablate both Numb and its homologue Numbl. The trabecular bone mass decreased dramatically while the cortical bone mass was unaffected. Here, the Notch signal was not activated,while the tensin homologue deleted on human chromosome 10(PTEN), which dephosphorylates phosphatidylinositide 3-kinases, was elevated, attenuating protein kinase B(Akt). The ubiquitination assay revealed that NUMB may physiologically promote PTEN ubiquitination in the presence of neural precursor cell-expressed developmentally downregulated protein 4–1. In addition, the deficiency of Numb/Numbl also activated the Hedgehog pathway through GLI1. This process was found to improve the ratio of the receptor activator of nuclear factor-k B ligand to osteoprotegerin, which enhanced the differentiation of osteoclasts and bone resorption. In conclusion, this study provides an insight into new functons of NUMB and NUMBL on bone homeostasis.

关键词： NUMB maintains bone mass by promoting degradation of PTEN and GLI1 via ubiquitination in osteoblasts GLI RANKL

Rho/Rock signal transduction pathway is required for MSC tenogenic differentiation

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Bone Research 2015年第3期3卷 173-181页

作者： Edward Maharam Miguel Yaport Nathaniel L Villanueva Takintope Akinyibi Damien Laudier Zhiyong He Daniel J Leong Hui B Sun Leni and Peter W.May Department of Orthopedics Icahn School of Medicine at Mount Sinai Departments of Orthopedic Surgery Albert Einstein College of Medicine Radiation Oncology Albert Einstein College of Medicine

Mesenchymal stem cell （MSC）-based treatments have shown promise for improving tendon healing and repair. MSCs have the potential to differentiate into multiple lineages in response to select chemical and physical stimuli, including into tenocytes. Cell elongation and cytoskeletal tension have been shown to be instrumental to the process of MSC differentiation. Previous studies have shown that inhibition of stress fiber formation leads MSCs to default toward an adipogenic lineage, which suggests that stress fibers are required for MSCs to sense the environmental factors that can induce differentiation into tenocytes. As the Rho/ROCK signal transduction pathway plays a critical role in both stress fiber formation and in cell sensation, we examined whether the activation of this pathway was required when inducing MSC tendon differentiation using rope-like silk scaffolds. To accomplish this, we employed a loss-of-function approach by knocking out ROCK, actin and myosin （two other components of the pathway） using the specific inhibitors Y-27632, Latrunculin A and blebbistatin, respectively. We demonstrated that independently disrupting the cytoskeleton and the Rho/ ROCK pathway abolished the expression of tendon differentiation markers and led to a loss of spindle morphology. Together, these studies suggest that the tension that is generated by MSC elongation is essential for MSC teno-differentiation and that the Rho/ROCK pathway is a critical mediator of tendon differentiation on rope-like silk scaffolds.

关键词： MSCs Figure Rho/Rock signal transduction pathway is required for MSC tenogenic differentiation

Cancer-directed surgery in malignant pleural mesothelioma: extrapleural pneumonectomy and pleurectomy/decortication

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Journal of Cancer Metastasis and Treatment 2021年第1期7卷 938-949页

作者： Brian Housman Andrea S.Wolf Department of Thoracic Surgery Icahn School of Medicine at Mount SinaiNew York 10029USA.

Malignant pleural mesothelioma(MPM)is a primary solid malignancy related to inhalational asbestos *** advances in therapy,MPM remains challenging to treat with a post-treatment survival of only 15%at *** recent years,extra-pleural pneumonectomy has decreased in popularity due to a high morbidity rate and mortality compared to pleurectomy/decortication and other therapeutic *** this review,we will discuss both procedures,outcomes,ongoing studies,and the roles of surgery in the future treatment of this disease.

关键词： Surgery for malignant pleural mesothelioma extrapleural pneumonectomy pleurectomy/decortication recurrence perioperative mortality

Beta-adrenergic agonist protects retinal pigment epithelium against hydroxycholoroquine toxicity via c AMP-PKA signal pathway

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International Journal of Ophthalmology(English edition) 2020年第4期13卷 552-559页

作者： Ruihua Zhang Dan-Ning Hu Richard Rosen Eye and Vision Research Institute Department of OphthalmologyIcahn School of Medicine at Mount SinaiNew York 10029USA Department of Ophthalmology New York Eye and Ear Infirmary of Mount SinaiNew York 10003USA

AIM: To test our hypothesis that activation of protein kinase A(PKA) signal pathway by β-adrenergic agonist plays an important role in the protecting of cultured retinal pigment epithelial(RPE) cells against the hydroxychloroquine(HCQ) toxicity. METHODS: Cultured human RPE cells were treated with 1) HCQ, 2) HCQ with salbutamol(a β2-adrenergic receptor agonist), and 3) HCQ with salbutamol and a PKA inhibitor, and compared these to 4) untreated cells(controls). After treated for 24 h, cell vacuolation, cells viability, PKA and PKA kinase activity levels were determined by the measurement of the size of vacuoles using Image J software, the cell counting with a dye-exclusion testing, Western blot and PKA kinase detection, respectively. RESULTS: Cell vacuolation and cell death of cultured RPE cells were significantly increased by the treatment of HCQ. Salbutamol significantly elevated PKA and PKA activity levels and this was associated with the inhibition of the vacuolation and cell death. The PKA inhibitor significantly decreased the PKA levels and eliminated the protective effects of salbutamol on HCQ-treated RPE cells. CONCLUSION: The PKA pathway plays an important role in the protective effects of β2-adrenergic agonist on the RPE cells against HCQ toxicity. These findings reveal a novel potential strategy against HCQ retinopathy by treatment with PKA activating medications.

关键词： hydroxycholoroquine retinal pigment epithelial cells retinopathy protein kinase A vacuolation

Plasma and wound fluid levels of eight proangiogenic proteins are elevated after colorectal resection

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World Journal of Gastrointestinal Oncology 2019年第6期11卷 470-488页

作者： HMC Shantha Kumara Xiao-Hong Yan Erica Pettke Vesna Cekic Nipa Dilip Gandhi Geoffrey A Bellini Richard L Whelan Division of Colon and Rectal Surgery Department of SurgeryMount Sinai West HospitalNew YorkNY 10019United States Department of Surgery Mount Sinai Icahn School of MedicineNew YorkNY 10029United States

BACKGROUND Colorectal resection is associated with 3-5 wk long elevations in the plasma levels of at least 11 proangiogenic proteins that may stimulate tumor angiogenesis *** increases during the first week after surgery may be related to the acute inflammatory response;the cause(s)of the week 2-5 increases is *** wounds are a possible source because of the important role that angiogenesis plays in the healing *** main hypothesis of the study is that wound fluid levels of the proteins studied will be elevated well beyond plasma levels which,in turn,are elevated from preoperative baseline *** To determine plasma and wound fluid levels of 8 proangiogenic proteins after colorectal resection for cancer and benign *** Blood and wound fluid samples were taken simultaneously on postoperative(postop)day 1,3,and later time points until wound drain removal in 35 colorectal cancer patients and 31 benign disease patients undergoing colorectal resection in whom closed wound drains had been placed in either the pelvis or the subcutaneous space of the abdominal *** plasma levels were compared to preop plasma and postop wound fluid levels(separate analyses for cancer and benign groups).RESULTS Sixty-six colorectal disease patients were studied(35 cancer,31 benign pathology).Most patients underwent minimally invasive surgery(open surgery in 11%of cancer and 6%of benign patients).The majority in the cancer group had rectal resections while in the benign group sigmoid or right colectomy *** levels of all 8 proteins were significantly elevated from baseline (P<0.05) at all post-operative time points in the cancer group and at 90% of time points(29/32) in the benign *** levels of all 8 proteins were 3-106 times higher (P<0.05) than plasma levels at 87-90 percent of postop time points;of note,wound levels were more than 10 times higher at 47-50% of time *** Plasma protein levels were elevat

关键词： Effects of surgery Colorectal resection Colorectal cancer Plasma protein levels Wound protein levels Angiogenesis

Clostridium diffi cile associated infection,diarrhea and colitis

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World Journal of Gastroenterology 2009年第13期15卷 1554-1580页

作者： Perry Hookman Jamie S Barkin University of Miami Miller school of medicine Division of Gastroenterology Mount Sinai Medical Center

A new,hypervirulent strain of Clostridium difficile,called NAP1/BI/027,has been implicated in *** cile outbreaks associated with increased morbidity and mortality since the early *** epidemic strain is resistant to fluoroquinolones in vitro,which was infrequent prior to *** name of this strain reflects its characteristics,demonstrated by different typing methods:pulsed-field gel electrophoresis(NAP1),restriction endonuclease analysis(BI) and polymerase chain reaction(027).In 2004 and 2005,the US Centers for Disease Control and Prevention(CDC) emphasized that the risk of *** icile-associated diarrhea(CDAD) is increased,not only by the usual factors,including antibiotic exposure,but also gastrointestinal surgery/manipulation,prolonged length of stay in a healthcare setting,serious underlying illness,immune-compromising conditions,and *** on proton pump inhibitors(PPIs) have an elevated risk,as do peripartum women and heart transplant *** 2002,toxic megacolon in *** cile-associated colitis(CDAC),was rare,but its incidence has increased *** to twothirds of hospitalized patients may be infected with *** *** carriers admitted to healthcare facilities can transmit the organism to other susceptible patients,thereby becoming *** colitis is reported more frequently during outbreaks of *** cile infection in patients with inflammatory bowel disease(IBD).*** infection with IBD carries a higher mortality than without underlying *** article reviews the latest information on *** cile infection,including presentation,vulnerable hosts and choice of antibiotics,alternative therapies,and probiotics and *** review contact precautions for patients with known or suspected *** *** institutions require accurate and rapid diagnosis for early detection of possible outbreaks,to initiate specific therapy and implement effective control mea

关键词：结肠炎腹泻胃肠病学医院感染