• Bibliometrics
• Humans
• Dermatology/statistics & numerical data
• Organ Transplantation/adverse effects
• Skin Neoplasms/etiology
• Periodicals as Topic/statistics & numerical data

• Adénorcarcinome de prostate
• Immunosuppresseurs
• Immunosuppression
• Prostate cancer
• Solid organ transplant recipient
• Transplantation

• Humans
• Male
• Prostatic Neoplasms/therapy
• Prostatic Neoplasms/epidemiology
• Prostatic Neoplasms/diagnosis
• Prostatic Neoplasms/mortality
• Middle Aged
• Retrospective Studies
• Aged
• Organ Transplantation/adverse effects
• Immunosuppressive Agents/therapeutic use
• Immunosuppressive Agents/adverse effects
• Prostatectomy
• Transplant Recipients/statistics & numerical data

• actinic keratosis
• skin cancer
• prevention
• non-invasive imaging
• pro score

• basal cell carcinoma
• keratinocyte carcinoma
• non-melanoma skin cancer
• squamous cell carcinoma

• aging
• cancer
• chemoprevention
• lung
• rapamycin

• Mice
• Animals
• Sirolimus/pharmacology
• Sirolimus/therapeutic use
• Everolimus/pharmacology
• Aging
• Carcinogens/pharmacology
• Lung Neoplasms/chemically induced
• Lung Neoplasms/prevention & control
• Lung Neoplasms/drug therapy

• UNOS/OPTN
• end stage renal disease (ESRD)
• renal transplantation (RT)
• risk factors
• skin cancer

Aging constitutes progressive physiological changes in an organism. These changes alter the normal biological functions, such as the ability to manage metabolic stress, and eventually lead to cellular senescence. The process itself is characterized by nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These hallmarks are risk factors for pathologies, such as cardiovascular diseases, neurodegenerative diseases, and cancer. Emerging evidence has been focused on examining the genetic pathways and biological processes in organisms surrounding these nine hallmarks. From here, the therapeutic approaches can be addressed in hopes of slowing the progression of aging. In this review, data have been collected on the hallmarks and their relative contributions to aging and supplemented with in vitro and in vivo antiaging research experiments. It is the intention of this article to highlight the most important antiaging strategies that researchers have proposed, including preventive measures, systemic therapeutic agents, and invasive procedures, that will promote healthy aging and increase human life expectancy with decreased side effects.

• aging
• antiaging strategies
• hallmarks
• risk factors
• therapeutic agent

• Chronic exposure
• Histology
• Neuroprotective dose
• Rapamycin
• mTOR

• Animals
• Humans
• Immunosuppressive Agents/adverse effects
• Mice
• Mice, Inbred C57BL
• Neuroprotective Agents/pharmacology
• Neuroprotective Agents/therapeutic use
• Paraquat
• Sirolimus/pharmacology
• Sirolimus/therapeutic use

• Heart transplantation
• immunosuppression
• incidence
• lymphoma
• mortality
• prevalence

• Calcineurin Inhibitors/adverse effects
• Graft Rejection/prevention & control
• Graft Survival
• Immunosuppressive Agents/adverse effects
• Kidney Transplantation/adverse effects
• TOR Serine-Threonine Kinases

• Mammalian target of rapamycin inhibitors(mTORi)
• Non-melanoma skin cancers (NMSCs)
• Solid-organ transplant recipients (SOTRs)
• Squamous cell carcinoma (SCC)
• immunosuppression

There has been a considerable improvement in post-transplant care since the early 1960s. Some patients we meet in the clinic have personally experienced this progress and have histories to tell that one must not forget. This is the brief history of a long-time “transplant survivor.”

In 1970, a young woman developed acute oedema, proteinuria, hypertension and oliguria during pregnancy. Labor was induced, but neither the child nor the kidney function could be saved. Our patient started dialysis, and 4 years later received a kidney transplant donated by her father (then 55 years of age). Maintenance immunosuppression consisted of prednisolone and azathioprine until 2011, when azathioprine was switched to everolimus due to skin cancer. Before this, our patient was highly satisfied with prednisolone/azathioprine, despite discussions regarding newer immunosuppressive drugs, and always reminded the treating physician that one should “never change a winning team.” Retrospectively, the avoidance of calcineurin inhibitors might have been beneficial for this patient who still has preserved an excellent renal function with s-creatinine levels around 100 μmol/L and just had sparse fibrosis detected in a recently performed transplant biopsy. The transplanted kidney is now 101 years old and is still working 24/7.

Our patient received a kidney transplant for 46 years ago and still has a remarkably stable transplant function with s-creatinine levels around 100 μmol/L. This case report illustrates the potential endurance of the kidneys and is a reminder to keep taking individualized treatment decisions even though new treatment alternatives promise superiority.

• biopsy
• history
• immunosuppressants
• kidney
• transplantation - kidney

Background: A significant proportion of lupus nephritis patients develop chronic kidney disease (CKD) and progressive kidney fibrosis, for which there is no specific treatment. We previously reported that mycophenolate or rapamycin monotherapy showed comparable efficacy in suppressing kidney fibrosis in a murine model of lupus nephritis through their direct action on mesangial cells. We extended our study to investigate the effect of combined mycophenolate and rapamycin treatment (MR) on kidney fibrosis in NZBWF1/J mice.

Methods: Female NZBWF1/J mice with active nephritis were randomized to receive vehicle or treatment with mycophenolate (50 mg/kg/day) and rapamycin (1.5 mg/kg/day) (MR) for up to 12 weeks, and the effect of treatment on clinical parameters, kidney histology, and fibrotic processes was investigated.

Results: Progression of nephritis in untreated mice was accompanied by mesangial proliferation, glomerulosclerosis, tubular atrophy, protein cast formation, increased mTOR and ERK phosphorylation, and induction of TGF-β1, IL-6, α-smooth muscle actin, fibronectin, and collagen expression. Combined MR treatment prolonged survival, improved kidney function, decreased anti-dsDNA antibody level, and ameliorated histopathological changes. The effect of combined MR treatment on kidney histology and function was comparable to that of mycophenolate or rapamycin monotherapy. In vitro studies in human mesangial cells showed that exogenous TGF-β1 and IL-6 both induced mTOR and ERK phosphorylation and downstream fibrotic processes. Both mycophenolic acid and rapamycin inhibited inflammatory and fibrotic processes induced by TGF-β1 or IL-6 by downregulating mTOR and ERK phosphorylation.

Conclusions: Our findings indicate that combined mycophenolate and rapamycin, at reduced dose, improves kidney fibrosis in murine lupus nephritis through their distinct effect on mTOR and ERK signaling in mesangial cells.

• fibrosis
• lupus nephritis
• mesangial cells
• mycophenolate
• rapamycin

• Cancer
• Immunosuppression
• Immunotherapy
• Kidney transplantation
• Multiple myeloma

• Heart transplantation
• Immunosuppression

• Calcineurin Inhibitors/therapeutic use
• Graft Rejection/prevention & control
• Humans
• Immunosuppression Therapy
• Immunosuppressive Agents/adverse effects
• Organ Transplantation/adverse effects
• Steroids

Astrocytes are a main target of JC polyomavirus (JCPyV) in the central nervous system (CNS), where the destruction of these cells, along with oligodendrocytes, leads to the fatal disease progressive multifocal leukoencephalopathy (PML). There is no cure currently available for PML, so it is essential to discover antivirals for this aggressive disease. Additionally, the lack of a tractable in vivo models for studying JCPyV infection makes primary cells an accurate alternative for elucidating mechanisms of viral infection in the CNS. This research to better understand the signaling pathways activated in response to JCPyV infection reveals and establishes the importance of the PI3K/AKT/mTOR signaling pathway in JCPyV infection in primary human astrocytes compared to transformed cell lines. Using RNA sequencing and chemical inhibitors to target PI3K, AKT, and mTOR, we have demonstrated the importance of this signaling pathway in JCPyV infection of primary astrocytes not observed in transformed cells. Collectively, these findings illuminate the potential for repurposing drugs that are involved with inhibition of the PI3K/AKT/mTOR signaling pathway and cancer treatment as potential therapeutics for PML, caused by this neuroinvasive virus.

• AKT
• JC polyomavirus
• PI3K
• PML
• SVGA cells
• astrocytes
• mTOR
• primary cells
• rapamycin
• wortmannin

Background: One of the important causes of mortality and morbidity in kidney transplanted patients is Post Transplant Lymphoproliferative Disease (PTLD), which is due to immunosuppression therapy and viral activity. It seems that Rapamycin, with dual antineoplastic and immunosuppressive effects, may have a pivotal role in the treatment of PTLD patients and preserving transplanted kidneys.

Methods and Materials: Twenty patients with PTLD were enrolled. Immunosuppressive therapy was reduced or ceased, and Rapamycin was initiated at the time of PTLD diagnosis. We evaluated the effects of switching immunosuppressive drugs to Rapamycin on graft status, the response of tumor, and 6, 12 months, and 5-year survival in patients.

Results: PTLD remission was achieved in 14 patients, while six patients died; no relapse was detected in recovered patients. The median of PTLD free time was 25 months, and the mean overall survival in patients with PTLD treated by Rapamycin was 84.8 (95% CI=61.3-108.23).The five-year survival rate was 67%, 12 months survival was 73.8%, and six months' survival was 80%. The response rate to Rapamycin and immunosuppression reduction alone was 46.6%. Four out of 13 Diffuse Large B-Cell Lymphoma patients achieved a complete response just only after the reduction of immunosuppressive drugs and the consumption of Rapamycin.

Conclusion: The present study demonstrated the effectiveness of conversion from immunosuppressive medication, particularly of Calcineurin inhibitors to Rapamycin in PTLD patients. However, more research is needed to confirm the Rapamycin effect on patients with PTLD.

• Lymphoma
• Post-transplant lymphoproliferative disorders
• Rapamycin
• Renal transplant M-TOR inhibitors

• aldara
• cutaneous squamous cell carcinoma (cSCC)
• imiquimod
• interleukin-2 (IL2)
• intralesional
• intralesional IL-2
• intralesional immunotherapy
• organ transplant recipient

• Administration, Cutaneous
• Aged
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/adverse effects
• Carcinoma, Squamous Cell/drug therapy
• Carcinoma, Squamous Cell/immunology
• Graft Rejection/prevention & control
• Humans
• Imiquimod/administration & dosage
• Imiquimod/adverse effects
• Immunocompromised Host
• Immunosuppression Therapy/adverse effects
• Infusions, Intralesional
• Interleukin-2/administration & dosage
• Interleukin-2/adverse effects
• Kidney Transplantation
• Liver Transplantation
• Male
• Neoplasm Recurrence, Local/drug therapy
• Skin Neoplasms/drug therapy
• Skin Neoplasms/immunology
• Transplant Recipients
• Treatment Outcome

• Cancer
• Gender
• Kidney transplantation
• Risk factor
• Sex

Patients receiving a solid organ transplantation, such as a kidney, liver, or lung transplantation, inevitably have to take drugs to suppress the immune system in order to prevent rejection of the transplanted organ. However, these drugs are known to cause malignancies in the long term. This study focuses specifically on newly developed carcinomas in patients who use those drugs after a solid organ transplantation. This systematic review and meta-analysis of published data show a 20-fold risk to develop a carcinoma after solid organ transplantation compared to the general population, with specifically increased risks in patients who receive cyclosporine or azathioprine. By comparing the different pathways involved in immunosuppression and the occurrence of carcinoma development, new insights can be discovered for future research and understanding of carcinoma development in transplantation patients and the general population as well.

Immunosuppressive therapy after solid organ transplantation leads to the development of cancer in many recipients. Analysis of the occurrence of different types of de novo carcinomas in relation to specific immunosuppressive drugs may give insight into their carcinogenic process and carcinogenesis in general. Therefore, a systematic search was performed in Embase and PubMed. Studies describing over five de novo carcinomas in patients using immunosuppressive drugs after solid organ transplantation were included. Incidence per 1000 person-years was calculated with DerSimonian–Laird random effects model and odds ratio for developing carcinomas with the Mantel–Haenszel test. Following review of 5606 papers by title and abstract, a meta-analysis was conducted of 82 studies. The incidence rate of de novo carcinomas was 8.41. Patients receiving cyclosporine developed more de novo carcinomas compared to tacrolimus (OR1.56, 95%CI 1.00–2.44) and mycophenolate (OR1.26, 95%CI 1.03–1.56). Patients receiving azathioprine had higher odds to develop de novo carcinomas compared to mycophenolate (OR3.34, 95%CI 1.29–8.65) and head and neck carcinoma compared to tacrolimus (OR3.78, 95%CI 1.11–12.83). To conclude, patients receiving immunosuppressive drugs after solid organ transplantation have almost a 20-fold increased likelihood of developing carcinomas, with the highest likelihood for patients receiving cyclosporine A and azathioprine. Looking into altered immune pathways affected by immunosuppressive drugs might lead to better understanding of carcinogenesis in general.

• carcinoma
• epidemiologic studies
• immunosuppression
• organ transplantation

• Kaposi's sarcoma
• Kidney transplantation
• Paclitaxel
• Sarcome de Kaposi
• Transplantation rénale

• immunosuppressant
• kidney transplantation
• malignancy
• mammalian target of rapamycin inhibitor (mTORI)
• outcomes

During the coronavirus disease 2019 (Covid-19) pandemic, several physicians have questioned pursuing belatacept in kidney-transplant patients in order to reduce the risk of nosocomial transmission during the monthly infusion. The effect of the conversion from belatacept to another immunosuppressive regimen is underreported. The aim of the present retrospective study was to assess the effect on kidney function and the clinical outcome of the conversion from belatacept to another regimen.

We have identified 44 maintenance kidney transplantation patients from five French kidney transplantation centers who were converted from belatacept to another regimen either because of a complication (n = 28) or another reason (patients’ request or belatacept shortage, n = 13). The follow-up after the conversion from belatacept was 27.5 ± 25.3 months.

Overall, mean estimated glomerular filtration rate (eGFR) decreased from 44.2 ± 16 ml/min per 1.73 m² at conversion from belatacept to 35.7 ± 18.4 ml/min per 1.73 m² at last follow-up (P = 0.0002). eGFR significantly decreased in patients who had been given belatacept at transplantation as well as in those who had been converted to belatacept earlier. The decrease was less significant in patients who had stopped belatacept without having experienced any complications. Finally, eGFR decreased more severely in patients who were converted to calcineurin inhibitors (CNIs), compared to those who received mammalian target of rapamycin inhibitor (mTORi). Few patients also developed diabetes and hypertension.

Thus, transplantation physicians should avoid stopping belatacept when not clinically required.

• belatacept
• calcineurin inhibitor
• conversion
• donor-specific antibody
• kidney function
• safety

To provide real-world data and summarize current clinical evidence on the efficacy and safety of sirolimus in active systemic lupus erythematosus (SLE) patients.

This was a prospective real-world clinical study. Included SLE patients should have Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) ⩾ 2. They were treated with sirolimus and followed up regularly. The SLEDAI-2K, Physician Global Assessment (PGA), serological activity indices, and remission of organ manifestations were evaluated. We also performed a meta-analysis to integrate current evidence of sirolimus in SLE.

A total of 49 patients were included in the final analysis. After treatment, the SLEDAI-2K (6.2 ± 3.1 versus 4.0 ± 3.4, p = 0.001) decreased significantly, and the prednisone dosage was tapered successfully (9.9 ± 8.8 mg/day versus 5.9 ± 4.0 mg/day, p = 0.002). Serological activity indices also improved [complement 3 (C3): 0.690 ± 0.209 g/l versus 0.884 ± 0.219 g/l, p < 0.001; complement 4: 0.105 ± 0.059 g/l versus 0.141 ± 0.069 g/l, p < 0.001; anti-dsDNA antibody, 200 ± 178 IU/ml versus 156 ± 163 IU/ml, p = 0.022]. The remission proportions of arthritis, skin rash, and thrombocytopenia were 100%, 88.8%, and 46.2%, respectively. A total of 41.2% of lupus nephritis (LN) patients achieved renal remission, but the average 24-h urine protein level was not significantly changed. Meta-analysis enrolled five studies with 149 patients included, and revealed similar results regarding the changes of SLEDAI-2K [−3.5 (−5.0, −2.1)], C3 [0.224 (0.136, 0.311) g/l] and daily dosage of prednisone [−12.7 (−19.9, −5.6) mg/day].

Sirolimus might be effective and tolerated in SLE. The role of sirolimus in LN requires further study.

• lupus nephritis
• mTOR inhibitor
• sirolimus
• systemic lupus erythematosus
• thrombocytopenia
• treatment

• Cancer
• Graft Function
• Kidney Transplantation
• Malignancy
• Mortality

• Adult
• Female
• Graft Rejection/prevention & control
• Humans
• Immunosuppressive Agents/therapeutic use
• Kidney Transplantation
• Male
• Middle Aged
• Neoplasms/complications
• Renal Insufficiency, Chronic/complications
• Renal Insufficiency, Chronic/surgery
• Retrospective Studies
• Risk Factors
• Transplantation, Homologous
• Treatment Outcome

• 2017R1D1A1B03031642 National Research Foundation of Korea

• cancer
• kidney disease
• onconephrology

The mechanistic target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation and survival in response to the availability of energy sources and growth factors. Cancer development and progression is often associated with constitutive activation of the mTOR pathway, thus justifying mTOR inhibition as a promising approach to cancer treatment and prevention. However, development of previous rapamycin analogues has been complicated by their induction of adverse side effects and variable efficacy. Since mTOR pathway regulation involves multiple feedback mechanisms that may be differentially activated depending on the degree of mTOR inhibition, we investigated whether rapamycin dosing could be adjusted to achieve chemopreventive efficacy without side effects. Thus, we tested the efficacy of two doses of a novel, highly bioavailable nanoformulation of rapamycin, Rapatar, in a mouse prostate cancer model (male mice with prostate epithelium-specific Pten-knockout). We found that the highest efficacy was achieved by the lowest dose of Rapatar used in the study. While both doses tested were equally effective in suppressing proliferation of prostate epithelial cells, higher dose resulted in activation of feedback circuits that reduced the drug’s tumor preventive efficacy. These results demonstrate that low doses of highly bioavailable mTOR inhibitor, Rapatar, may provide safe and effective cancer prevention.

• PTEN
• mTOR
• prevention
• prostate cancer
• rapamycin

• COVID-19
• SARS-CoV-2
• coronavirus
• rapalog
• sirolimus

• Age Factors
• Aged
• Aged, 80 and over
• COVID-19
• COVID-19 Testing
• COVID-19 Vaccines
• Clinical Laboratory Techniques
• Coronavirus Infections/diagnosis
• Coronavirus Infections/drug therapy
• Coronavirus Infections/immunology
• Coronavirus Infections/physiopathology
• Coronavirus Infections/prevention & control
• Coronavirus Infections/therapy
• Humans
• Immunosenescence
• Pandemics/prevention & control
• Pneumonia, Viral/immunology
• Pneumonia, Viral/physiopathology
• Pneumonia, Viral/prevention & control
• Pneumonia, Viral/therapy
• Viral Vaccines
• COVID-19 Drug Treatment

• aging
• anti-aging
• fasting
• health span
• lifespan
• metformin
• rapalogs
• rapamycin

• Prior cancers
• kidney transplant
• melanoma
• myeloma
• transplant suitability

Colorectal cancer (CRC) occurs with more aggressiveness in kidney transplant recipients compared to the general population. Immunosuppressive therapy plays a crucial role in the development of post-transplant malignancy. Concretely, cyclosporine A (CsA) has intrinsic pro-oncologic properties, while several studies report a regression of cancer after the introduction of rapamycin (RAPA). However, their effect on the extracellular vesicle (EV) content from CRC cell lines and their relevance in the pre-metastatic niche have not yet been studied. Here, we investigated the effect of RAPA and CsA in EV-miRNAs from metastatic and non-metastatic CRC cell lines and the role of relevant miRNAs transferred into a pre-metastatic niche model. EV-miRNA profiles showed a significant upregulation of miR-6127, miR-6746-5p, and miR-6787-5p under RAPA treatment compared to CsA and untreated conditions in metastatic cell lines that were not observed in non-metastatic cells. From gene expression analysis of transfected lung fibroblasts, we identified 22 shared downregulated genes mostly represented by the histone family involved in chromatin organization, DNA packaging, and cell cycle. These results suggest that EV-miR-6127, miR-6746-5p and miR-6787-5p could be a potential epigenetic mechanism induced by RAPA therapy in the regulation of the pre-metastatic niche of post-transplant colorectal cancer.

• cancer
• gender
• immunosuppression
• kidney transplant
• risk factor

• Ornithine decarboxylase
• Post-transcriptional regulation
• mRNA stability
• mTOR

• Kaposi sarcoma
• chemotherapy
• immunosuppression
• mTOR inhibitor
• organ transplantation
• post-transplant malignancies

• Aged
• Female
• Humans
• Immunosuppressive Agents/administration & dosage
• Immunosuppressive Agents/adverse effects
• Incidence
• Liver Transplantation/adverse effects
• Liver Transplantation/mortality
• Male
• Middle Aged
• Neoplasms/diagnosis
• Neoplasms/epidemiology
• Neoplasms/mortality
• Neoplasms/therapy
• Retrospective Studies
• Risk Factors
• Time Factors
• Treatment Outcome
• Turkey/epidemiology

• merkel cell carcinoma
• immunosuppression
• hiv/aids
• cll
• solid organ transplant
• outcomes

• Adult
• Aged
• Aged, 80 and over
• Autoimmune Diseases/complications
• Carcinoma, Merkel Cell/immunology
• Carcinoma, Merkel Cell/mortality
• Carcinoma, Merkel Cell/therapy
• Cohort Studies
• Female
• HIV Infections/complications
• Humans
• Immune Tolerance
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasm Recurrence, Local/therapy
• Organ Transplantation
• Retrospective Studies
• Salvage Therapy
• Skin Neoplasms/immunology
• Skin Neoplasms/mortality
• Skin Neoplasms/therapy

• P01 CA225517 NCI NIH HHS
• P30 CA015704 NCI NIH HHS

Previous studies show that mTOR inhibitors decrease the risk of cancer development after kidney transplantation. However, the effect of cumulative doses of mTOR inhibitors on cancer after kidney transplantation is not well known.

In the current study, patients were registered into a national database in Taiwan. Between year 2000 and 2013, 4,563 patients received kidney transplantation. They were divided into two groups, according to mTOR inhibitors usage. The cumulative dose of mTOR inhibitors was recorded. Patients were followed-up until de novo cancer development, death, or the end of 2014.

Patients were divided into two groups: mTOR inhibitors users (study group, n = 828) and mTOR inhibitors non-users (control group, n = 3,735). The median follow-up duration was 7.8 years. The risk of de novo cancer (hazards ratio (HR) 0.80, 95% CI [0.60–1.09], p = 0.16) and risk of death (HR 1.14, 95% CI [0.82–1.60], p = 0.43) was not different between mTOR inhibitor user and non-user groups. Neither high- nor low-dose exposure to mTOR inhibitors was associated with increased risk of cancer or mortality. Analysis of cancer subtypes showed no influence by mTOR inhibitors. In addition, the cause of mortality was not significantly different between the two groups.

We could not find the association of mTOR inhibitors use and risk of de novo cancer development or mortality in patients with kidney transplantation in Chinese patients. Cumulative exposure to mTOR inhibitors did not change the results.

• Cancer
• Chronic kidney disease
• Kidney transplantation
• Mortality
• mTOR inhibitors