Growth inhibition of high-intensity focused ultrasound on hepatic cancer in vivo

AIM： To investigate the damaging effect of high-intensity focused ultrasound （HIFU） on cancer cells and the inhibitory effect on tumor growth. METHODS： Hurine H22 hepatic cancer cells were treated with HIFU at the same intensity for different lengths of time and at different intensities for the same length oftime in vitro, the dead cancer cells were determined by trypan blue staining. Two groups of cancer cells treated with HIFU at the lowest and highest intensity were inoculated into mice. Tumor masses were removed and weighed after 2 wk, tumor growth in each group was confirmed pathologically.RESULTS： The death rate of cancer cells treated with HIFU at 1 000 W/cm^2 for 0.5, 1, 2, 4, 8, and 12 s was 3.11±1.21%, 13.37±2.56%, 38.84±3.68%, 47.22±5.76%,87.55±7.32%, and 94.33±8.11%, respectively. A positive relationship between the death rates of cancer cells and the length of HIFU treatment time was found （r = 0.96,P〈0.01）. The death rate of cancer cells treated with HIFU at the intensity of 100, 200, 400, 600, 800, and 1 000 W/cm^2 for 8 s was 26.31±3.26%, 31.00±3.87%, 41.97±5.86%,72.23±8.12%, 94.90±8.67%, and 99.30±9.18%, respectively. A positive relationship between the death rates of cancer cells and the intensities of HIFU treatment was confirmed （r= 0.98, P〈0.01）. The cancer cells treated with HIFU at 1 000 W/cm^2 for 8 s were inoculated intomice ed into. The tumor inhibitory rate was 90.35% compared to the control （P〈0.01）. In the experimental group inoculated with the cancer cells treated with HIFU at 1 000 W/cm^2 for 0.5 s, the tumor inhibitory rate was 22.9% （P〈0.01）. By pathological examination, tumor growth was confirmed in 8 out of 14 mice （57.14%, 8/14） inoculated with the cancer cells treated with HIFU at 1 000 W/cm^2 for 8 s, which was significantly lower than that in the control （100%, 15/15, P〈O.05）.CONCLUSION： HIFU is effective on killing or damage of H22 hepatic cancer cells in vitro and on inhibiting tumor growth in mice ex vivo.

Outcome of endotherapy for pancreas divisum in patients with acute recurrent pancreatitis

AIM: To assess the rate of relapses of acute pancreatitis (AP), recurrent AP (RAP) and the evolution of endosonographic signs of chronic pancreatitis (CP) in patients with pancreas divisum (PDiv) and RAP.

Colorectal cancer screening from 45 years of age: Thesis, antithesis and synthesis

Colorectal cancer incidence and mortality in patients younger than 50 years are increasing, but screening before the age of 50 is not offered in Europe. Advancedstage diagnosis and mortality from colorectal cancer before 50 years of age are increasing. This is not a detection-bias effect;it is a real issue affecting the entire population. Three independent computational models indicate that screening from 45 years of age would yield a better balance of benefits and risks than the current start at 50 years of age. Experimental data support these predictions in a sex- and race-independent manner. Earlier screening is seemingly affordable, with minimal impediments to providing younger adults with colonoscopy. Indeed, the American Cancer Society has already started to recommend screening from 45 years of age in the United States. Implementing early screening is a societal and public health problem. The three independent computational models that suggested earlier screening were criticized for assuming perfect compliance. Guidelines and recommendations should be derived from well-collected and reproducible data, and not from mathematical predictions. In the era of personalized medicine, screening decisions might not be based solely on age, and sophisticated prediction software may better guide screening. Moreover, early screening might divert resources away from older individuals with greater biological risks. Finally, it is still unknown whether early colorectal cancer is part of a continuum of disease or a biologically distinct disease and, as such, it might not benefit from screening at all. The increase in early-onset colorectal cancer incidence and mortality demonstrates an obligation to take actions. Earlier screening would save lives, and starting at the age of 45 years may be a robust screening option.

A novel expressed prostatic secretion(EPS)-urine metabolomic signature for the diagnosis of clinically significant prostate cancer

Objective:Significant efforts are currently being made to identify novel biomarkers for the diagnosis and risk stratification of prostate cancer(PCa).Metabolomics can be a very useful approach in biomarker discovery because metabolites are an important read-out of the disease when characterized in biological samples.We aimed to determine a metabolomic signature which can accurately distinguish men with clinically significant PCa from those affected by benign prostatic hyperplasia(BPH).Methods:We first performed untargeted metabolomics using ultrahigh-performance liquid chromatography tandem mass spectrometry on expressed prostatic secretion urine(EPS-urine)from 25 patients affected by BPH and 25 men with clinically significant PCa(defined as Gleason score≥3+4).Diagnosis was histologically confirmed after surgical treatment.The EPS-urine metabolomic approach was then applied to a larger,prospective cohort of 92 consecutive patients undergoing multiparametric magnetic resonance imaging for clinical suspicion of PCa prior to biopsy.Results:We established a novel metabolomic signature capable of accurately distinguishing PCa from benign tissue.A metabolomic signature was associated with clinically significant PCa in all subgroups of the Prostate Imaging Reporting and Data System(PI-RADS)classification(100%and 89.13%of accuracy when the PI-RADS was in range of 1–2 and 4–5,respectively,and 87.50%in the more critical cases when the PI-RADS was 3).Conclusions:A combination of metabolites and clinical variables can effectively help in identifying PCa patients that might be overlooked by current imaging technologies.Metabolites from EPS-urine should help in defining the diagnostic pathway of PCa,thus improving PCa detection and decreasing the number of unnecessary prostate biopsies.

Multidisciplinary management of patients diagnosed with von Hippel-Lindau disease: A practical review of the literature for clinicians

Objective:The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance,treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hippel-Lindau(VHL)syndrome.Methods:A non-systematic narrative review of original articles,meta-analyses,and random-ized trials was conducted,including articles in the pre-clinical setting to support relevant find-ings.Results:VHL disease is the most common rare hereditary disorder associated with clear cell renal cell carcinoma.Affected individuals inherit a germline mutation in one VHL allele,and any somatic event that disrupt the other allele can trigger mutations,chromosomal rearrange-ments,or epigenetic regulations leading to oncogenesis.From a clinical perspective,patients continuously develop multiple primary tumors.Conclusion:Because VHL is considered a rare disease,very limited evidence is available for diagnosis,surveillance,active treatment with local or systemic therapy and follow-up.

Primary lymphomas of the genitourinary tract:A population-based study

Objective:We performed a population-based analysis focusing on primary extranodal lymphoma of either testis,kidney,bladder or prostate(PGUL).Methods:We identified all cases of localized testis,renal,bladder and prostate primary lymphomas(PL)versus primary testis,kidney,bladder and prostate cancers within the Surveillance,Epidemiology,and End Results database(1998e2015).Estimated annual proportion change methodology(EAPC),multivariable logistic regression models,cumulative incidence plots and multivariable competing risks regression models were used.Results:The rates of testis-PL,renal-PL,bladder-PL and prostate-PL were 3.04%,0.22%,0.18%and 0.01%,respectively.Patients with PGUL were older and more frequently Caucasian.Annual rates significantly decreased for renal-PL(EAPC:5.6%;pZ0.004)and prostate-PL(EAPC:3.6%;pZ0.03).In multivariable logistic regression models,older ager independently predicted testis-PL(odds ratio[OR]:16.4;p<0.001)and renal-PL(OR:3.5;p<0.001),while female gender independently predicted bladder-PL(OR:5.5;p<0.001).In surgically treated patients,cumulative incidence plots showed significantly higher 10-year cancer-specific mortality(CSM)rates for testis-PL,renal-PL and prostate-PL versus their primary genitourinary tumors.In multivariable competing risks regression models,only testis-PL(hazard ratio[HR]:16.7;p<0.001)and renal-PL(HR:2.52;p<0.001)independently predicted higher CSM rates.Conclusion:PGUL rates are extremely low and on the decrease in kidney and prostate but stable in testis and bladder.Relative to primary genitourinary tumors,PGUL are associated with worse CSM for testis-PL and renal-PL but not for bladder-PL and prostate-PL,even after adjustment for other-cause mortality.

Robot-assisted adrenalectomy:Step-by-step technique and surgical outcomes at a high-volume robotic center

Objective In the last years,robotic surgery was introduced in several different settings with good perioperative results.However,its role in the management of adrenal masses is still debated.In order to provide a contribution to this field,we described our step-by-step technique for robotic adrenalectomy(RA)and related modifications according to the type of adrenal mass treated.Methods We retrospectively analyzed 27 consecutive patients who underwent RA at Onze-Lieve-Vrouw hospital(Aalst,Belgium)between January 2009 and October 2022.Demographic,intra-and post-operative,and pathological data were retrieved from our prospectively maintained institutional database.Continuous variables are summarized as median and interquartile range(IQR).Categorical variables are reported as frequencies(percentages).Results Twenty-seven patients underwent RA were included in the study.Median age,body mass index,and Charlson's comorbidity index were 61(IQR:49-71)years,26(IQR:24-29)kg/m^(2),and 2(IQR:0-3),respectively,and 16(59.3%)patients were male.Median tumor size at computed tomography scan was 6.0(IQR:3.5-8.0)cm.Median operative time and blood loss were 105(IQR:82-120)min and 175(IQR:94-250)mL,respectively.No intraoperative complications were recorded.Overall postoperative complications rate was 11.1%,with a postoperative transfusion rate of 3.7%.A total of 10(37.0%)patients harbored malignant adrenal masses.Among them,3(11.1%)had adrenocortical carcinoma,6(22.2%)secondary metastasis,and 1(3.7%)malignant pheochromocytoma on final pathological exam.Only 1(10.0%)patient had positive surgical margins.Conclusion We described our step-by-step technique for RA,which can be safely performed even in case of high challenging settings as malignant tumors,pheochromocytoma,and large masses.The standardization of perioperative protocol should be encouraged to maximize the outcomes of this complex surgical procedure.

The association of type and number of high-risk criteria with cancer-specific mortality in prostate cancer patients treated with radical prostatectomy

Objectives:This study aimed to test the association between of type and number of D'Amico high-risk criteria(DHRCs)with cancer-specific mortality(CSM)in high-risk prostate cancer patients treated with radical prostatectomy.Materials and methods:In the Surveillance,Epidemiology,and End Results database(2004–2016),we identified 31,281 radical prostatectomy patients with at least 1 DHRC,namely,prostate-specific antigen(PSA)>20 ng/mL(hrPSA),biopsy Gleason Grade Group(hrGGG)score of 4 and 5,or clinical tumor stage≥T3(hrcT).Multivariable Cox regression models and competing risks regression models(adjusting for other cause mortality)tested the association between DHRCs and 5-year CSM.Results:Of 31,281 patients,14,394(67%)exclusively harbored hrGGG,3189(15%)harbored hrPSA,and 1781(8.2%)harbored hrcT.Only 2132 patients(6.8%)harbored a combination of the 2 DHRCs,and 138(0.6%)had all 3 DHRCs.Five-year CSMrates ranged from 0.9%to 3.0%when any individual DHRC was present(hrcT,hrPSA,and hrGGG,in that order),1.6%to 5.9%when 2 DHRCs were present(hrPSA-hrcT,hrcT-hrGGG,and hrPSA-hrGGG,in that order),and 8.1%when all 3 DHRCs were present.Cox regression models and competing risks regression confirmed the independent predictor status of DHRCs for 5-year CSM that was observed in univariable analyses,with hazard ratios from 1.00 to 2.83 for 1 DHRC,2.35 to 5.88 for combinations of 2 DHRCs,and 7.13 for all 3 DHRCs.Conclusions:Within individual DHRCs,hrcT and hrPSA exhibited weaker effects than hrGGG did.Moreover,a dose-response effect was identified according to the number of DHRCs.Accordingly,the type and number of DHRCs allow further risk stratification within the high-risk subgroup.

LIM-domain-only 4(LMO4)enhances CD8^(+)T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling

High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials.Herein,we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8^(+)T cells.Using IFN-γproduction as a proxy for CD8^(+)T cell terminal differentiation,LMO4 emerged among the top hits inhibiting the development of effectors cells.Consistently,we found that Lmo4 was downregulated upon CD8^(+)T cell activation but maintained under culture conditions facilitating the formation of stem-like T cells.By employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8^(+)T cells,we enabled selective expansion and enhanced persistence of transduced cells,while limiting their terminal differentiation and senescence.LMO4 overexpression promoted transcriptional programs regulating stemness,increasing the numbers of stem-like CD8^(+)memory T cells and enhancing their polyfunctionality and recall capacity.When tested in syngeneic and xenograft tumor models,LMO4 overexpression boosted CD8^(+)T cell antitumor immunity,resulting in enhanced tumor regression.Rather than directly modulating gene transcription,LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21,inducing the expression of target genes(Tcf7,Socs3,Junb,and Zfp36)crucial for memory responses.CRISPR/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4,thereby abrogating the therapeutic benefit of LMO4 overexpression.These results establish LMO4 overexpression as an effective strategy to boost CD8^(+)T cell stemness,providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.

L.ong-term recovery of normal sexual function in lesticular cancer survivors

Testicular cancer （TC） is the most common solid cancer in men between the third and fourth decade of life. Due to successful treatment approaches, TC survivors （TCSs） have long life expectancy, but with numerous potential long-term sequelae, including sexual dysfunction. We investigated predictors of long-term normal sexual function （SF） recovery in TCSs. Sociodemographic, medical, and psychometric data were analyzed in 143 Caucasian-European TCSs, who underwent orchiectomy at a single institution. Health-significant comorbidities were scored with the Charlson Comorbidity Index （CCI）. Patients completed the International Index of Erectile Function （IIEF）. Statistical models tested the association between predictors （including age at surgery, body mass index, CCI, and adjuvant therapy： radiotherapy [RT], chemotherapy [CT], CT followed by retroperitoneal lymph node dissection [RPLND] and RPLND alone） and the long-term recovery of normal SF （defined as IIEF-erectile function [EF] ≥26, and sexual desire [SD], intercourse satisfaction [IS] orgasmic function [OF], and overall satisfaction [OS] domain scores in the upper tertiles）. At a mean follow-up of 86 months, 35 （25.5%） TCSs had erectile dysfunction （ED）, with 16 （11.2%） experiencing severe ED. Median time of EF recovery was 60, 60, and 70 months after CT, RT, and RPLND, respectively. Only adjuvant RT emerged as an independent predictor of nonrecovery of normal EF （HR： 0.55, P = 0.01）. Neither adjuvant CT nor CT plus RPLND or RPLND alone significantly impaired the recovery of normal erections. Adjuvant therapy was not associated with impaired recovery of normal sexuality as a whole, considering the IIEF-SD, -OF, -IS, and OS domains.

Substances of abuse consumption among patients seeking medical help for uro-andrological purposes:a sociobehavioral survey in the real-life scenario

Substances of abuse(SoA),as well as smoking and alcohol consumption,are well known for their impact on male fertility status,erectile function,and ejaculation.We assessed SoA consumption habits in a cohort of men seeking medical attention for uro-andrological purposes.Data from 7447 men seeking medical attention for the first time for uro-andrological purposes were analyzed.A complete medical and sexual history was collected for each patient.Smoking,alcohol,and SoA consumption were investigated.Descriptive statistics was used to describe the whole cohort.The primary motivations for their evaluation were lower urinary tract symptoms(LUTS),erectile dysfunction(ED),and infertility in 1912(25.7%),2944(39.5%),and 2591(34.8%)men,respectively.Previous use of SoA was reported by 378(5.1%)men,and 190(2.6%)individuals were current users.Patients seeking medical attention for infertility were more frequently current SoA users(107;4.1%)than men with ED(66;2.2%)and LUTS(17;0.9%)(both P<0.001).Current users of SoA were younger than those with past or no SoA history(P<0.001).Current SoA users were more frequently smokers(P<0.001)and alcohol consumers(P<0.001)than those with a previous history or those who had never tried SoA.In conclusion,approximately 3%of men seeking medical attention for uro-andrological purposes were current SoA consumers.Infertile men reported a higher use of SoA than those with ED or LUTS.Current SoA users were younger and more frequently concomitant smokers and alcohol consumers compared to those who did or had never used SoA.

Metabolic syndrome in White-European men presenting for secondary couple＇s infertility： an investigation of the clinical and reproductive burden

We aimed to determine the impact of metabolic syndrome （MetS） on reproductive function in men with secondary infertility, a condition that has received relatively little attention from researchers. Complete demographic, clinical, and laboratory data from 167 consecutive secondary infertile men were analyzed. Health-significant comorbidities were scored with the Charlson Comorbidity Index （CCI; categorised 0 vs I vs 2 or higher）. NCEP-ATP III criteria were used to define MetS. Semen analysis values were assessed based on the 2010 World Health Organization （WHO） reference criteria. Descriptive statistics and logistic regression models tested the association between semen parameters and clinical characteristics and MetS. MetS was found in 20 （12%） of 167 men. Patients with MetS were older （P 〈 0.001） and had a greater BMI （P 〈 0.001） compared with those without MetS. MetS patients had lower levels of total testosterone （P = 0.001）, sex hormone-binding globulin, inhibin B, and anti-MOIlerian hormone （all P 〈 0.03）, and they were hypogonadal at a higher prevalence （P = 0.01） than patients without MetS. Moreover, MetS patients presented lower values of semen volume, sperm concentration, and sperm normal morphology （all P≤0.03）. At multivariate logistic regression analysis, no parameters predicted sperm concentration, normal sperm morphology, and total progressive motility. Our data show that almost 1 of 8 White-European men presenting for secondary couple＇s infertility is diagnosed with MetS. MetS was found to be associated with a higher prevalence of hypogonadism, decreased semen volume, decreased sperm concentration, and normal morphology in a specific cohort of White-European men.

Sexual dysfunction and prostate cancer risk： one more piece of a complex puzzle

In an era of personalized medicine where genetic, environmental, and biometric factors are considered as a whole throughout the diagnostic and therapeutic approach to a disease, the association between several clinical factors and prostate cancer risk （PCa） has been thoroughly investigated. In the study ofZapata et al.,

Differences in rates of pelvic lymph node dissection in National Comprehensive Cancer Network favorable,unfavorable intermediate-and high-risk prostate cancer across United States SEER registries

Background:The National Comprehensive Cancer Network(NCCN)guidelines recommend pelvic lymph node dissection(PLND)in NCCN high-and intermediate-risk prostate cancer patients.We tested for PLND nonadherence(no-PLND)rates within the Surveillance Epidemiology and End Results(2010-2015).Materials and methods:We identified all radical prostatectomy patients who fulfilled the NCCN PLND guideline criteria(n=23,495).Nonadherence rates to PLND were tabulated and further stratified according to NCCN risk subgroups,race/ethnicity,geographic distribution,and year of diagnosis.Results:Overall,the no-PLND rate was 26%;it was 41%,25%,and 11%in the NCCN intermediate favorable,intermediate unfavorable,and high-risk prostate cancer patients,respectively(p<0.001).Overtime,the no-PLND rates declined in the overall cohort and within each NCCN risk subgroup.Georgia exhibited the highest no-PLND rate(49%),whereas New Jersey exhibited the lowest(15%).Finally,no-PLND race/ethnicity differences were recorded only in the NCCN intermediate unfavorable subgroup,where Asians exhibited the lowest no-PLND rate(20%)versus African Americans(27%)versus Whites(26%)versus Hispanic-Latinos(25%).Conclusions:The lowest no-PLND rates were recorded in the NCCN high-risk patients followed by NCCN intermediate unfavorable and favorable risk in that order.Our findings suggest that unexpectedly elevated differences in no-PLND rates warrant further examination.In all the NCCN risk subgroups,the no-PLND rates decreased over time.

Heavy cigarette smoking and alcohol consumption are associated with impaired sperm parameters in primary infertile men

We assessed the concomitant impact of cigarette smoking and alcohol con sumption in men presenting for primary couple's infertility.Data from 189 in fertile men were an a lyzed.Semen analysis,serum hormones,and sperm DNA fragmentation(SDF)were obtained.Smoking status was categorized as follows:current nonsmoker(-S),moderate smoker(+MS),and heavy smoker(+HS).Alcohol consumption was categorized as follows:abstainer(-D),moderate drinker(+MD),and heavy drinker(+HD).Descriptive statistics and logistic regression models were applied.Among all the participants,132(69.8%),30(15.9%),and 27(14.3%)patients were-S,+MS,and+HS,respectively.In addition,67(35.4%),77(40.7%)and 45(23.8%)men were-D,+MD and+HD,respectively.Regarding concomitant habits,52(27.5%)patients were nonsmokers and abstainers(-S/-D:Group 1),91(48.1%)had at least one recreational habit(-S/+D or+S/-D:Group 2),and 46(24.3%)were both smokers and drinkers(+S/+D:Group 3).Sperm concentration and progressive motility were lower in+HS and+HD,compared with-S and-D(all P<0.05),respectively.Similarly,both parameters were significantly lower in Group 3 than Groups 1 and 2(all P<0.05).SDF values were higher in Group 3 than Groups 1 and 2(both P<0.05).In multivariate analysis,follicle-stimulating hormone(FSH)levels and concomitant+S/+D status were independent predictors of impaired sperm concentration and progressive motility(all P<0.05).Heavy smoking and heavy drinking were associated with worse seminal parameters than moderate smoking/drinking and nonsmoking/abstaining.When concomitant,+S/+D status has an even greater detrimental effect on semen parameters.

NGR-tagged nano-gold： A new CD13-selective carrier for cytokine delivery to tumors

Colloidal gold （Au）, a well-tolerated several applications in nanomedicine. nanomaterial, is currently exploited for We show that gold nanoparticles tagged with a novel tumor-homing peptide containing Asn-Gly-Arg （NGR）, a ligand of CD13 expressed by the tumor neovasculature, can be exploited as carriers for cytokine delivery to tumors. Biochemical and functional studies showed that the NGR molecular scaffoldflinker used for gold functionalization is critical for CD13 recognition. Using fibrosarcorna-bearing mice, NGR-tagged nanodrugs could deliver extremely low, yet pharmacologically active doses of tumor necrosis factor （TNF）, an anticancer cytokine, to tumors with no evidence of toxicity. Mechanistic studies confirmed that CD13 targeting was a primary mechanism of drug delivery and excluded a major role of integrin targeting consequent to NGR deamidation, a degradation reaction that generates the isoAsp-Gly-Arg （isoDGR） integrin ligand. NGR-tagged gold nanoparticles can be used, in principle, as a novel platform for single- or multi-cytokine delivery to tumor endothelial cells for cancer therapy.

Testicular volume in infertile versus fertile white-European men: a case-control investigation in the real-life setting

Testicular volume(TV)is considered a good clinical marker of hormonal and spermatogenic function.Accurate reference values for TV measures in infertile and fertile men are lacking.We aimed to assess references values for TV in white-European infertile men and fertile controls.We analyzed clinical and laboratory data from 1940(95.0%)infertile men and 102(5.0%)fertile controls.Groups were matched by age using propensity score weighting.TV was assessed using a Prader orchidometer(PO).Circulating hormones and semen parameters were investigated in every male.Descriptive statistics,Spearman's correlation,and logistic regression models tested potential associations between PO-estimated TV values and clinical variables.Receiver operating characteristic(ROC)curves were used to find TV value cutoffs for oligoasthenoteratozoospermia(OAT)and nonobstructive azoospermia(NOA)status in infertile men.The median testicular volume was smaller in infertile than that of fertile men(15.0 ml vs 22.5 ml;P<0.001).TV positively correlated with total testosterone,sperm concentration,and progressive sperm motility(all P≤0.001)in infertile men.At multivariable logistic regression analysis,infertile status(P<0.001)and the presence of left varicocele(P<0.001)were associated with TV<15 ml.Testicular volume thresholds of 15 ml and 12 ml had a good predictive ability for detecting OAT and NOA status,respectively.In conclusion,infertile men have smaller testicular volume than fertile controls.TV positively correlated with total testosterone,sperm concentration,and progressive motility in infertile men,which was not the case in the age-matched fertile counterparts.

SUMOylation regulates p27^(Kip1) stability and localization in response to TGFβ

Exposure of normal and tumor-derived cells to TGFbresults in different outcomes,depending on the regulation of key targets.The CDK inhibitor p27^(Kip1) is one of these TGFβ targets and is essential for the TGFβ-induced cell cycle arrest.TGFb treatment inhibits p27^(Kip1) degradation and induces its nuclear translocation,through mechanisms that are still unknown.Recent evidences suggest that SUMOylation,a post-translational modification able to modulate the stability and subcellular localization of target proteins,critically modifies members of the TGFβ signaling pathway.Here,we demonstrate that p27^(Kip1) is SUMOylated in response to TGFβ treatment.Using different p27^(Kip1) point mutants,we identified lysine 134(K134)as the residue modified by small ubiquitin-like modifier 1(SUMO1)in response to TGFb treatment.TGFβ-induced K134 SUMOylation increased protein stability and nuclear localization of both endogenous and exogenously expressed p27^(Kip1).We observed thatSUMOylation regulated p27^(Kip1) binding to CDK2,thereby governing its nuclear proteasomal degradation through the phosphorylation of threonine 187.Importantly,p27^(Kip1) SUMOylation was necessary for proper cell cycle exit following TGFbtreatment.These data indicate thatSUMOylation is a novel regulatory mechanism that modulates p27^(Kip1) function in response to TGFβ stimulation.Given the involvement of TGFb signaling in cancer cell proliferation and invasion,our data may shed light on an important aspect of this pathway during tumor progression.

Vascular occlusion to protect against intraoperative blood loss in liver surgeries: new perspectives on a traditional technique

The correlation between decreased blood loss and improved clinical and oncological outcomes has been described in liver surgery:considering that perioperative blood transfusions are associated with a higher rate of recurrence and lower survival after resection of colorectal liver metastases and hepatocellular carcinoma,any effort to address the task of bleeding control and reduce the need for blood transfusions is of outstanding importance(1).