Neuro-11:a new questionnaire for the assessment of somatic symptom disorder in general hospitals

Background Somatic symptom disorder(SSD)commonly presents in general hospital settings,posing challenges for healthcare professionals lacking specialised psychiatric training.The Neuro-11 Neurosis Scale(Neuro-11)offers promise in screening and evaluating psychosomatic symptoms,comprising 11 concise items across three dimensions:somatic symptoms,negative emotions and adverse events.Prior research has validated the scale’s reliability,validity and theoretical framework in somatoform disorders,indicating its potential as a valuable tool for SSD screening in general hospitals.Aims This study aimed to establish the reliability,validity and threshold of the Neuro-11 by comparing it with standard questionnaires commonly used in general hospitals for assessing SSD.Through this comparative analysis,we aimed to validate the effectiveness and precision of the Neuro-11,enhancing its utility in clinical settings.Methods Between November 2020 and December 2021,data were collected from 731 patients receiving outpatient and inpatient care at Shenzhen People’s Hospital in China for various physical discomforts.The patients completed multiple questionnaires,including the Neuro-11,Short Form 36 Health Survey,Patient Health Questionnaire 15 items,Hamilton Anxiety Scale and Hamilton Depression Scale.Psychiatry-trained clinicians conducted structured interviews and clinical examinations to establish a gold standard diagnosis of SSD.Results The Neuro-11 demonstrated strong content reliability and structural consistency,correlating significantly with internationally recognised and widely used questionnaires.Despite its brevity,the Neuro-11 exhibited significant correlations with other questionnaires.A test-retest analysis yielded a correlation coefficient of 1.00,Spearman-Brown coefficient of 0.64 and Cronbach’sαcoefficient of 0.72,indicating robust content reliability and internal consistency.Confirmatory factor analysis confirmed the validity of the three-dimensional structure(p<0.001,comparative fit index=0.94,Tucker-Lewis index=0.92,root mean square error of approximation=0.06,standardised root mean square residual=0.04).The threshold of the Neuro-11 is set at 10 points based on the maximum Youden’s index from the receiver operating characteristic curve analysis.In terms of diagnostic efficacy,the Neuro-11 has an area under the curve of 0.67.

International study of the Complex Stress Reaction Syndrome:Implications for transdiagnostic clinical practice

BACKGROUND The debate regarding diagnostic classification systems in psychiatry(categorial vs dimensional systems)has essential implications for the diagnosis,prevention and treatment of stress reactions.We previously found a unique pattern of stress reaction in a study executed during the coronavirus disease 2019 pandemic using large representative samples in two countries,and termed it the Complex Stress Reaction Syndrome(CSRS).AIM To investigate CSRS,Type A(psychiatric symptoms,spanning anxiety,depression,stress symptoms,and posttraumatic stress disorder(PTSD)),with or without long-coronavirus disease(COVID)residuals(CSRS,Type B,neuropsychiatric symptoms spanning cognitive deficits and fatigue,excluding systemic symptoms).Our two-tailed hypothesis was that CSRS is a condition related to an unrecognized type of stress reaction in daily life in the general population(Type A)or that it is related to the severe acute respiratory syndrome coronavirus 2 infection and its long-COVID residuals(Type B).METHODS 977 individuals in four continents(North America,Europe,Australia and the Middle East)completed the online study questionnaire in six languages using the Qualtrics platform.The study was managed by six teams in six countries that promoted the study on social media.The questionnaire assessed anxiety,depression,stress symptoms and PTSD(CSRS,Type A),cognitive deficits and fatigue(CSRS,Type B).The data were analyzed using Proportion Analyses,Multivariate Analysis of Co-Variance(MANCOVA),linear regression analyses and validated clinical cutoff points.RESULTS The results of the Proportion Analyses showed that the prevalence of 4 symptoms spanning anxiety,depression,stress symptoms,and PTSD was significantly higher than the most prevalent combinations of fewer symptoms across 4 continents,age groups,and gender.This supports the transdiagnostic argument embedded in the CSRS(Type A).The same pattern of results was found in infected/recovered individuals.The prevalence of the 4 psychiatric symptoms combination was significantly greater than that of 5 and 6 symptoms,when adding cognitive deficits and fatigue,respectively.MANCOVA showed a significant three-way interaction(age×gender×continent).Further analyses showed that the sources of this three-way interaction were threefold relating to two sub-populations at-risk:(1)Individuals that self-identified as non-binary gender scored significantly higher on all 4 psychiatric symptoms of the CSRS,Type A at young age groups(<50 years old)in North America compared to(self-identified)women and men located in the 4 continents studied,and to other ages across the adult life span;and(2)This pattern of results(CSRS,Type A)was found also in women at young ages(<40 years old)in North America who scored higher compared to men and women in other continents and other ages.Linear regression analyses confirmed the MANCOVA results.CONCLUSION These results show a combined mental health risk factor related to stress reactivity,suggesting that the CSRS is sensitive to populations at risk and may be applied to future identification of other vulnerable sub-populations.It also supports the transdiagnostic approach for more accurate prevention and treatment.Time will tell if such transdiagnostic syndromes will be part of the discussions on the next revisions of the traditional classification systems or whether the crisis in psychiatry further evolves.

A systematic review of cytoreductive prostatectomy outcomes and complications in oligometastatic disease

Objective: To analyze outcomes and complications of cytoreductive prostatectomy (CRP) for oligometastatic prostate cancer (PCa) in order to elucidate its role in this space.Methods: We performed a systematic literature search using three databases (Medline, Scopus, and Web of Science). The primary endpoints were oncologic outcomes. The secondary endpoints were complication rates and functional results.Results: In all studies, overall survival was better or at least comparable variable in the groups with CRP compared to no local treatment. The greatest benefit from CRP in 5-year overall survival in one study was 67.4% for CRP versus 22.5% for no local treatment. Cancer-specific survival (CSS) showed the same trend. Several authors found significant benefits from CSS in the CRP group: from 79% vs. 46% to 100% vs. 61%. CRP was a predictor of better CSS (hazard ratio 0.264, p=0.004). Positive surgical margin rates differed widely from 28.6% to 100.0%. Urinary continence in CRP versus RP for localized PCa was significantly lower (57.4% vs. 90.8%, p<0.0001). Severe incontinence occurred seldom (2.5%-18.6%). Total complication rates after CRP differed widely, from 7.0% to 43.6%. Rates of grades 1 and 2 events prevailed. Patients on ADT alone also showed a considerable number of complications varying from 5.9% to 57.7%.Conclusion: CRP improves medium-term cancer control in patients with oligometastatic PCa. The morbidity and complication rates of this surgery are comparable with other approaches, but postoperative incontinence rate is higher compared with RP for localized disease.

Influence of vitamin D on liver fibrosis in chronic hepatitis C: A systematic review and meta-analysis of the pooled clinical trials data

AIM To investigate the relationship between vitamin D and liver fibrosis in hepatitis C-monoinfected or hepatitis C virus(HCV)-human immunodeficiency virus(HIV) coinfected patients. METHODS Pertinent studies were located by a library literature search in PubM ed/Embase/Cochrane/Scopus/LILACS by two individual reviewers. Inclusion criteria:(1) studies with patients with HCV or co-infected HCV/HIV;(2) studies with patients ≥ 18 years old;(3) studies that evaluated liver fibrosis stage, only based on liver biopsy; and(4) studies that reported serum or plasma 25(OH)D levels. Studies that included pediatric patients, other etiologies of liver disease, or did not use liver biopsy for fibrosis evaluation, or studies with inadequate data were excluded. Estimated measures of association reported in the literature, as well as corresponding measures of uncertainty, were recorded and corresponding odds ratios with 95%CI were included in a meta-analysis. RESULTS The pooled data of this systematic review showed that 9 of the 12 studies correlated advanced liver disease defined as a Metavir value of F3/4 with 25(OH) D level insufficiency. The meta-analysis indicated a significant association across studies.CONCLUSION Low vitamin D status is common in chronic Hepatitis C patients and is associated with advanced liver fibrosis.

Vitamin D levels do not predict the stage of hepatic fibrosis in patients with non-alcoholic fatty liver disease: A PRISMA compliant systematic review and meta-analysis of pooled data

AIM To investigate the relationship between 25-hydroxyvitamin D [25(OH)D] levels and fibrosis stage in patients with non-alcoholic fatty liver disease(NAFLD).METHODS Two individual reviewers identified relevant studies using the Pub Med, EMBASE, Cochrane, and Scopus databases. Inclusion criteria were as follows:(1) Studies that evaluated adults with NAFLD and serum or plasma 25(OH)D levels; and(2) assessed fibrosis stage using liver biopsy. A rigorous analysis yielded six articles as having sufficient data to employ in evaluating the association of serum vitamin D levels in patients with NAFLD based on their liver fibrosis stage by histopathological analysis. The lead investigators of each of the six studies were contacted and the data were collected. To meta-analyze vitamin D levels in F0-F2 vs F3-F4 fibrosis, a random-effects meta-analysis fit using restricted maximum likelihood was applied. To examine trends across each stage of fibrosis with respect to vitamin D levels, a meta-regression was performed. P < 0.05 was considered statistically significant. RESULTS A total of 937 subjects from six studies were included in the final analysis to evaluate the association of serum vitamin D levels in patients with NAFLD based on their liver fibrosis stage by histopathological analysis. The lead investigators of each of the six studies were contacted and the data were collected. First, the investigators performed a meta-analysis to compare serum vitamin D levels in patients with NAFLD with stage F0-F2 compared to F3-F4, which did not show significance [meta-estimate of the pooled mean difference =-0.86, P = 0.08(-4.17, 2.46)]. A metaregression evaluation of serum vitamin 25(OH)D levels across the individual stages(F0-F4) of fibrosis did not show an association for the six included studies.CONCLUSION Low vitamin D status is not associated with higher stages of liver fibrosis in patients with NAFLD.

Differences in characteristics of patients with and without known risk factors for hepatocellular carcinoma in the United States

AIM： To examine the clinical characteristics of a subgroup of patients with hepatocellular carcinoma （HCC） and compare them to those with known risk factors. METHODS： We used the HCC database of 306 patients seen at our institution from January 1, 1995 to December 31, 2001. Of the 306 patients, 63 （20%, group 1） had no known risk factors （hepatitis C virus, hepatitis B virus, alcohol, hemochromatosis or cirrhosis from any cause） and 243 （group 2） had one or more risk factors. RESULTS： The median age was similar in both groups, but there were disproportionate numbers of younger （〈 30 years old）, older （〉 80 years） patients, women （33% vs 18%）, and Caucasians （81% vs 52%） in group 1 as compared to group 2. There were fewer Asians （2% vs 11%） and African Americans （13% vs 27%） in group 1. Abdominal pain （70% vs 37%） was more common while gastrointestinal bleeding （0% vs 11%） and ascites （4% vs17%） were less common in group i compared to group 2. Group 1 had larger tumor burden （median size 9.4 cm vs 5.7 cm） at the time of presentation, but there were no differences in the site （right, left or bilateral lesions）, or number of tumors between the two groups. CONCLUSION： HCC patients without identifiable risk factors have different characteristics and clinical presentation compared to those with known risk factors.Absence of cirrhosis and larger tumor burden may explain the differences in the presenting symptoms.

Neutralization of excessive levels of active TGF-β1 reduces MSC recruitment and differentiation to mitigate peritendinous adhesion

PPeritendinous adhesion formation(PAF)can substantially limit the range of motion of digits.However,the origin of myofibroblasts in PAF tissues is still unclear.In this study,we found that the concentration of active TGF-β1 and the numbers of macrophages,mesenchymal stromal cells(MSCs),and myofibroblasts in human and mouse adhesion tissues were increased.Furthermore,knockout of TGF-β1 in macrophages or TGF-β1R2 in MSCs inhibited PAF by reducing MSC and myofibroblast infiltration and collagenⅠandⅢdeposition,respectively.Moreover,we found that MSCs differentiated into myofibroblasts to form adhesion tissues.Systemic injection of the TGF-β–neutralizing antibody 1D11 during the granulation formation stage of PAF significantly reduced the infiltration of MSCs and myofibroblasts and,subsequently,PAF.These results suggest that macrophage-derived TGF-β1 recruits MSCs to form myofibroblasts in peritendinous adhesions.An improved understanding of PAF mechanisms could help identify a potential therapeutic strategy.

Novel approaches for the molecular classification of prostate cancer

Among the urologic cancers, prostate cancer is by far the most common, and it appears to have the potential to affect almost all men throughout the world as they age. A number of studies have shown that many men with prostate cancer will not die from their disease, but rather with the disease but from other causes. These men have a form of prostate cancer that is described as ＂very low risk＂ and has often been called indolent.

Long-term outcomes of postgastrectomy syndrome after total laparoscopic distal gastrectomy using the augmented rectangle technique

BACKGROUND For total laparoscopic distal gastrectomies for gastric cancer,the reconstruction method is critical to the clinical outcome of the procedure.However,which reconstruction technique is optimal remains controversial.We originally reported the augmented rectangle technique(ART)as a reconstruction option for total laparoscopic Billroth I reconstructions.Still,little is known about its effect on long-term outcomes,specifically the incidence of postgastrectomy syndrome and its impact on quality of life.AIM To analyze postgastrectomy syndrome and quality of life after ART using the Postgastrectomy Syndrome Assessment Scale-37(PGSAS-37)questionnaire.METHODS At Juntendo University,a total of 94 patients who underwent ART for Billroth I reconstruction with total laparoscopic distal gastrectomies for gastric cancer between July 2016 and March 2020 completed the PGSAS-37 questionnaire.Multidimensional analysis was performed,comparing those 94 ART cases from our institution(ART group)to 909 distal gastrectomy cases with a Billroth I reconstruction from other Japanese institutions who also completed the PGSAS-37 as part of a larger national database(PGSAS group).RESULTS Patients in the ART group had significantly better total symptom scores in all the symptom subscales(i.e.,esophageal reflux,abdominal pain,meal-related distress,indigestion,diarrhea,constipation,and dumping).The loss of body weight was marginally greater for those in the ART group than in the PGSAS group(-9.3%vs-7.9%,P=0.054).The ART group scored significantly lower in their dissatisfaction of ongoing symptoms,during meals,and with daily life.CONCLUSION ART for Billroth I reconstruction provided beneficial long-term results for postgastrectomy syndrome and quality of life in patients undergoing total laparoscopic distal gastrectomies for gastric cancer.

Present and future of immune checkpoint blockade: Monotherapy to adjuvant approaches

Immune regulation of aggressive tumor growth is often outpaced by tumor up-regulation of ligands that inhibit effector immune responses through the activation of immune checkpoints. A few of such checkpoints include programmed death-1(PD-1), cytotoxic T lymphocyte associated antigen-4(CTLA-4), lymphocyte activation gene-3, T-cell immunoglobulin and mucin protein-3, Glucocorticoid-induced TNFR family-related receptor(GITR), and killer cell immunoglobulin like receptor. With the exception of GITR, after binding to their respective ligands these checkpoints induce down-modulation of immune responses to prevent autoimmunity. However, such immune mechanisms are co-opted by tumors to allow rapid tumor cell proliferation. Pre-clinical studies in antibody blockade of PD-1 and CTLA-4 have led to promising augmentation of effector immune responses in murine tumor models, and human antibodies against PD-1 and CTLA-4 alone or in combination have demonstrated tumor regression in clinical trials. The development of immune checkpoint blockade as a potential future immunotherapy has led to increasing interest in combining treatment modalities. Combination checkpoint blockade with chemotherapy and radiation therapy has shown synergistic effects in pre-clinical and clinical studies, and combination checkpoint blockade with bacterial vaccine vectors have produced increased effector immune responses in pre-clinical models. The future of immune checkpoint blockade may be as a powerful adjuvant alongside the current standard of care.

A Single Therapeutic miRNA Rescues the Oncolysis of Androgen Activated Prostate Specific Virus in Androgen Independent Cell Model

Prostate specific conditionally replicating adenoviruses (CRAd) are made by placing a tissue specific promoter upstream of one or more of the viral genes required for replication (e.g., E1A, E1B). However, one major problem associated with these vectors is their dependency for androgen receptor (AR), to transactivate the immediate early gene of the virus. This absolute necessity of androgens for prostate specific promoters renders them less useful in patients that have undergone or are currently on total androgen ablation therapy. Therefore, an alternative approach is needed for the existing vectors to be useful in clinical settings. To overcome this problem, we have generated a prostate specific CRAd by introducing a single therapeutic miRNA (miR-34c) that was identified in our library screen to synergize with viral oncolysis. Overexpression of miR-34c from the backbone of virus not only helped in suppressing the proliferation of AR positive cells but also rescued the oncolysis of androgen activated prostate specific virus in androgen independent cell model. To our knowledge this is the first report describing the utility of a single therapeutic miRNA construct to rescue viral oncolysis in advanced androgen resistant AR negative prostate cancer cell line model.

Helping to address the over treatment of prostate cancer： tools to differentiate lethal and non-lethal phenotype in prostate cancer

2011 was a noteworthy year for those interested in the care of patients with prostate cancer. First, the US Preventive Services Task Force （USPSTF） released an update on prostate cancer screening, and recommended against the use of the prostate-specific antigen （PSA） test for all men, regardless of family history or race. While this surprised many in the field, the conclusion that there is more harm than benefit is inescapable on a population level--the focus of the USPSTF. Most men with newly diagnosed prostate cancer have favorable risk disease and are at an age when treatment is unlikely to extend life---a conclusion that is supported by randomized trials. Second, the National Institutes of Health convened a ＇State of the Science＇ conference on active surveillance for prostate cancer, and concluded that the rates of overtreatment of prostate cancer are high and surveillance is greatly underutilized. Both the USPSTF and the National Institutes of Health conference were prompted in large part by the recognition that widespread PSA testing leads to prostate biopsies that often uncover indolent disease. In the majority of cases,

Analytical Optimization of GeneXpert Ultra for Detection of Tuberculosis in CSF Samples

Detection of Mycobacterium tuberculosis complex (MTBC) in extrapulmonary specimens can be challenging due to their paucibacillary nature. This difficulty is especially true for cerebrospinal fluid (CSF), and the low sensitivity and specificity for diagnosis hampers rapid detection and treatment in vulnerable populations. GeneXpert MTB/RIF Ultra has been shown to provide rapid results for detection of MTBC and associated Rifampin resistance, but there is limited data regarding standardized methods for CSF processing on this assay. In this study, we sought to provide guidance regarding the best methods for CSF processing, including optimal volumes to test, length of incubation with sample reagent and finally effects of long-term freezing on detection.

Outcomes of patients with cirrhosis undergoing non-hepatic surgery:Risk assessment and management

The reported mortality rates in patients with cirrhosis undergoing various non-transplant surgical procedures range from 8.3% to 25%. This wide range of mortality rates is related to severity of liver disease, type of surgery, demographics of patient population, expertise of the surgical, anesthesia and intensive care unit team and finally, reporting bias. In this article, we will review the pathophysiology, morbidity and mortality associated with non-hepatic surgery in patients with cirrhosis, and then recommend an algorithm for risk assessment and evidence based management strategy to optimize post-surgical outcomes.

Selective lateral lymph node dissection after neoadjuvant chemoradiotherapy in rectal cancer

BACKGROUND Lateral lymph node metastasis is one of the leading causes of local recurrence in patients with advanced mid or low rectal cancer.Neoadjuvant chemoradiotherapy(NCRT)can effectively reduce the postoperative recurrence rate;thus,NCRT with total mesorectal excision(TME)is the most widely accepted standard of care for rectal cancer.The addition of lateral lymph node dissection(LLND)after NCRT remains a controversial topic.AIM To investigate the surgical outcomes of TME plus LLND,and the possible risk factors for lateral lymph node metastasis after NCRT.METHODS This retrospective study reviewed 89 consecutive patients with clinical stage II-III mid or low rectal cancer who underwent TME and LLND from June 2016 to October 2018.In the NCRT group,TME plus LLND was performed in patients with short axis(SA)of the lateral lymph node greater than 5 mm.In the non-NCRT group,TME plus LLND was performed in patients with SA of the lateral lymph node greater than 10 mm.Data regarding patient demographics,clinical workup,surgical procedure,complications,and outcomes were collected.Multivariate logistic regression analysis was performed to evaluate the possible risk factors for lateral lymph node metastasis in NCRT patients.RESULTS LLN metastasis was pathologically confirmed in 35 patients(39.3%):26(41.3%)in the NCRT group and 9(34.6%)in the non-NCRT group.The most common site of metastasis was around the obturator nerve(21/35)followed by the internal iliac artery region(12/35).In the NCRT patients,46%of patients with SA of LLN greater than 7 mm were positive.The postoperative 30-d mortality rate was 0%.Two(2.2%)patients suffered from lateral local recurrence in the 2-year follow up.Multivariate analysis showed that cT4 stage(odds ratio[OR]=5.124,95%confidence interval[CI]:1.419-18.508;P=0.013),poor differentiation type(OR=4.014,95%CI:1.038-15.520;P=0.044),and SA≥7 mm(OR=7.539,95%CI:1.487-38.214;P=0.015)were statistically significant risk factors associated with LLN metastasis.CONCLUSION NCRT is not sufficient as a stand-alone therapy to eradicate LLN metastasis in lower rectal cancer patients and surgeons should consider performing selective LLND in patients with greater LLN SA diameter,poorer histological differentiation,or advanced T stage.Selective LLND for NCRT patients can have a favorable oncological outcome.

Inhibition of cyclooxygenase-2 activity in subchondral bone modifies a subtype of osteoarthritis

Osteoarthritis(OA) causes the destruction of joints. Its pathogenesis is still under investigation, and there is no effective diseasemodifying therapy. Here, we report that elevated cyclooxygenase-2(COX-2) expression in the osteocytes of subchondral bone causes both spontaneous OA and rheumatoid arthritis(RA). The knockout of COX-2 in osteocytes or treatment with a COX-2 inhibitor effectively rescues the structure of subchondral bone and attenuates cartilage degeneration in spontaneous OA(STR/Ort)mice and tumor necrosis factor-α transgenic RA mice. Thus, elevated COX-2 expression in subchondral bone induces both OAassociated and RA-associated joint cartilage degeneration. The inhibition of COX-2 expression can potentially modify joint destruction in patients with arthritis.

Differentiating intraductal papillary mucinous neoplasms from other pancreatic cystic lesions

Intraductal papillary mucinous neoplasms(IPMN) can be difficult to distinguish from other cystic lesions of the pancreas.To understand better and discuss the current knowledge on this topic,the literature and the institutional experience at a large pancreatic disease center have been reviewed.A combination of preoperative demographic,historical,radiographic,laboratory data,as well as postoperative pathologic analyses can often distinguish IPMN from other lesions in the differential diagnosis.

Clinical utility of cerebrovascular reactivity mapping in patients with low grade gliomas

AIM:To evaluate neurovascular uncoupling(NVU)associated with low grade gliomas(LGG)using blood oxygen level dependent(BOLD)cerebrovascular reactivity mapping.METHODS:Seven patients with low grade gliomas referred by neurosurgeons for presurgical mapping were included in this pilot study.Cerebrovascular reactivity(CVR)mapping was performed by acquiring BOLD images while patients performed a block-design breath-hold(BH)hypercapnia task.CVR mapping was expressed as BOLD percentage signal change(PSC)from baseline associated with performance of the BH hypercapnia task.Standard T2*Dynamic Susceptibility Contrast perfusion imaging was performed and relative cerebral blood volume(rCBV)and relative cerebral blood flow(rCBF)maps were generated.Structural T1 weighted MR images were also acquired.A correlation analysis between intratumoral normalized(via ratio with contralateral homologous regions)BOLD BH PSC[referred to as(nCVR)]and intratumoral normalized resting state rCBV(rCBF)values(i.e.,nCBV and nCBF,respectively)was performed.RESULTS:No significant correlation was seen between the normalized BOLD BH PSC(i.e.,nCBV)and nCBV or nCBF.However,the average nCVR(median=0.50,z=-2.28,P=0.01)was significantly less than 1.0,indicating abnormally reduced vascular responses in the tumor regions relative to normal contralesional homologous regions,whereas the average nCBV(median=0.94,z=-0.92,P=0.375)and nCBF(median=0.93,z=-1.16,P=0.25)were not significantly higher or lower than 1.0,indicating iso-perfusion in the tumor regions relative to normal contralesional homologous regions.These findings suggest that in LGG,hyperperfusion that is seen in high grade gliomas is not present,but,nevertheless,abnormally decreased regional CVR is present within and adjacent to LGG.Since the patients all demonstrated at least some residual function attributable to the cortical regions of impaired CVR,but were incapable of producing a BOLD response in these regions regardless of the tasks performed,such regionally decreased CVR is indicative of NVU.The low nCVR ratios indicate high prevalence of NVU in this LGG cohort,which is an important consideration in the interpretation of clinical presurgical mapping with functional magnetic resonance(MR)imaging.CONCLUSION:Our preliminary study shows that BH CVR mapping is clinically feasible and demonstrates an unexpectedly high prevalence of NVU in patients with LGG.

Albumin-linked prostate-specific antigen-activated thapsigargin- and niclosamide-based molecular grenades targeting the microenvironment in metastatic castration-resistant prostate cancer

Localized prostate cancer is curable via annihilation of the entire cancer neighborhood by surgery or local radiation.Unfortunately,once metastatic,no available therapy is curative.The vast majority will die despite aggressive systemic combinational androgenablation therapies.Thus,there is an urgent need for effective systemic therapeutics that sterilize the entire microenvironment in metastatic castration-resistant prostate cancer(mCRPC).To accomplish this goal,advantage can be taken of the unique biology of mCRPC cells.Like their normal cell of origin,mCRPCs retain expression of the prostate-specific differentiation protein,prostate-specific antigen(PSA),which they abundantly secrete into their extracellular fluid(ECF).This unique,and essentially universal,secretion of enzymatically active PSA into the ECF by mCRPCs creates an exploitable therapeutic index for activation of systemically delivered highly lipophilic toxins as“molecular grenades”covalently linked to cysteine-34 of human serum albumin(HSA)via a stable maleimide containing PSA cleavable peptide such that PSA-dependent hydrolysis(i.e.,“detonation”)releases the grenades restrictively within the ECF of mCRPC.This approach decreases dose-limiting host toxicity while enhancing plasma half-life from minutes to days(i.e.,pharmacokinetic effect)and increasing the tissue concentration of the maleimide coupled albumin delivery(MAD)in the ECF at sites of cancer due to the enhanced permeability of albumin at these sites(i.e.,enhanced permeability and retention effect).This allows the MAD-PSA detonated grenades to circulate throughout the body in a non-toxic form.Only within sites of mCRPC is there a sufficiently high level of enzymatically active PSA to efficiently“pull the pin”on the grenades releasing their lipophilic cellpenetrant toxins from HSA.Thus,if a sufficient level of“detonation”occurs,this will kill mCRPC cells,and sterilize the entire PSA-rich metastatic sites via a bystander effect.In this review,two examples of such MAD-PSA detonated molecular grenades are presenteddone based upon thapsigagin and the other on niclosamide.

Effect of surgical procedures on prostate tumor gene expression profiles

Current surgical treatment of prostate cancer is typically accomplished by either open radical prostatectomy （ORP） or robotic-assisted laparoscopic radical prostatectomy （RALRP）. Intra-operative procedural differences between the two surgical approaches may alter the molecular composition of resected surgical specimens, which are indispensable for molecular analysis and biomarker evaluation. The objective of this study is to investigate the effect of different surgical procedures on RNA quality and genome-wide expression signature. RNA integrity number （RIN） values were compared between total RNA samples extracted from consecutive LRP （n= 11） and ORP （n= 24） prostate specimens. Expression profiling was performed using the Agilent human whole-genome expression microarrays. Expression differences by surgicat type were analyzed by Volcano plot analysis and gene ontology analysis. Quantitative reverse transcription （RT）-PCR was used for expression validation in an independent set of LRP （n=8） and ORP （n=8） samples. The LRP procedure did not compromise RNA integrity. Differential gene expression by surgery types was limited to a small subset of genes, the number of which was smaller than that expected by chance. Unexpectedly, this small subset of differentially expressed genes was enriched for those encoding transcription factors, oxygen transporters and other previously reported surgery-induced stress-response genes, and demonstrated unidirectional reduction in LRP specimens in comparison to ORP specimens. The effect of the LRP procedure on RNA quality and genome-wide transcript levels is negligible, supporting the suitability of LRP surgical specimens for routine molecular analysis. Blunted in vivo stress response in LRP specimens, likely mediated by CO2 insufflation but not by longer ischemia time, is manifested in the reduced expression of stress-response genes in these specimens.