Alternative ATPase domain interactions in eukaryotic Hsp70 chaperones.

Hsp70 molecular chaperones are essential components for maintaining protein homeostasis within cells. They interact with substrate or client proteins in a well characterised fashion that is regulated by ATP and supported by co-chaperones. In eukaryotes there is a vast array of Hsp70 isoforms that may facilitate adaption to a particular cellular compartment and distinct biological role. Emerging data indicate a novel type of interaction between Hsp70 and client protein that does not fit with the classical Hsp70 ATP regulated substrate mechanism. In this review, we highlight Hsp70 ATPase domain interactions with binding partners from various biological systems that we refer to as Hsp70 ATPase alternative binding proteins or HAAB proteins. We identify common mechanistic features that may define how Hsp70 operates when associating with proteins in this alternative HAAB mode of action.

Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer.

Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4's hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.

Temporal Profile of Descending Cortical Modulation of Spinal Excitability: Group and Individual-Specific Effects.

Sensorimotor control is modulated through complex interactions between descending corticomotor pathways and ascending sensory inputs. Pairing sub-threshold transcranial magnetic stimulation (TMS) with peripheral nerve stimulation (PNS) modulates the Hoffmann's reflex (H-reflex), providing a neurophysiologic probe into the influence of descending cortical drive on spinal segmental circuits. However, individual variability in the timing and magnitude of H-reflex modulation is poorly understood. Here, we varied the inter-stimulus interval (ISI) between TMS and PNS to systematically manipulate the relative timing of convergence of descending TMS-induced volleys with respect to ascending PNS-induced afferent volleys in the spinal cord to: (1) characterize effective connectivity between the primary motor cortex (M1) and spinal circuits, mediated by both direct, fastest-conducting, and indirect, slower-conducting descending pathways; and (2) compare the effect of individual-specific vs. standard ISIs. Unconditioned and TMS-conditioned H-reflexes (24 different ISIs ranging from -6 to 12 ms) were recorded from the soleus muscle in 10 able-bodied individuals. The magnitude of H-reflex modulation at individualized ISIs (earliest facilitation delay or EFD and individual-specific peak facilitation) was compared with standard ISIs. Our results revealed a significant effect of ISI on H-reflex modulation. ISIs eliciting earliest-onset facilitation (EFD 0 ms) ranged from -3 to -5 ms across individuals. No difference in the magnitude of facilitation was observed at EFD 0 ms vs. a standardized short-interval ISI of -1.5 ms. Peak facilitation occurred at longer ISIs, ranging from +3 to +11 ms. The magnitude of H-reflex facilitation derived using an individual-specific peak facilitation was significantly larger than facilitation observed at a standardized longer-interval ISI of +10 ms. Our results suggest that unique insights can be provided with individual-specific measures of top-down effective connectivity mediated by direct and/or fastest-conducting pathways (indicated by the magnitude of facilitation observed at EFD 0 ms) and other descending pathways that encompass relatively slower and/or indirect connections from M1 to spinal circuits (indicated by peak facilitation and facilitation at longer ISIs). By comprehensively characterizing the temporal profile and inter-individual variability of descending modulation of spinal reflexes, our findings provide methodological guidelines and normative reference values to inform future studies on neurophysiological correlates of the complex array of descending neural connections between M1 and spinal circuits.

The cerebral microvasculature: Basic and clinical perspectives on stroke and glioma.

Microvascular networks are vital components of the cardiovascular system, performing many key roles in maintaining the health and homeostasis of the tissues and organs in which they develop. As discussed in this review, the molecular and cellular components within the microcirculation orchestrate critical processes to establish functional capillary beds, including organization of endothelial cell (EC) polarity, guiding investment of vascular pericytes (PCs), and building the specialized extracellular matrix (ECM) that comprises the vascular basement membrane (vBM). Herein, we further discuss the unique features of the microvasculature in the central nervous system (CNS), focusing on the cells contributing to the neurovascular unit (NVU) that form and maintain the blood-brain barrier (BBB). With a focus on vascular PCs, we offer basic and clinical perspectives on neurovascular-related pathologies that involve defects within the cerebral microvasculature. Specifically, we present microvascular anomalies associated with glioblastoma multiforme (GBM) including defects in vascular-immune cell interactions and associated clinical therapies targeting microvessels (ie, vascular-disrupting/anti-angiogenic agents and focused ultrasound). We also discuss the involvement of the microcirculation in stroke responses and potential therapeutic approaches. Our goal was to compare the cellular and molecular changes that occur in the microvasculature and NVU, and to provide a commentary on factors driving disease progression in GBM and stroke. We conclude with a forward-looking perspective on the importance of microcirculation research in developing clinical treatments for these devastating conditions.

Integration of Convergent Sensorimotor Inputs Within Spinal Reflex Circuits in Healthy Adults.

The output from motor neuron pools is influenced by the integration of synaptic inputs originating from descending corticomotor and spinal reflex pathways. In this study, using paired non-invasive brain and peripheral nerve stimulation, we investigated how descending corticomotor pathways influence the physiologic recruitment order of the soleus Hoffmann (H-) reflex. Eleven neurologically unimpaired adults (9 females; mean age 25 ± 3 years) completed an assessment of transcranial magnetic stimulation (TMS)-conditioning of the soleus H-reflex over a range of peripheral nerve stimulation (PNS) intensities. Unconditioned H-reflex recruitment curves were obtained by delivering PNS pulses to the posterior tibial nerve. Subsequently, TMS-conditioned H-reflex recruitment curves were obtained by pairing PNS with subthreshold TMS at short (-1.5 ms) and long (+10 ms) intervals. We evaluated unconditioned and TMS-conditioned H-reflex amplitudes along the ascending limb, peak, and descending limb of the H-reflex recruitment curve. Our results revealed that, for long-interval facilitation, TMS-conditioned H-reflex amplitudes were significantly larger than unconditioned H-reflex amplitudes along the ascending limb and peak of the H-reflex recruitment curve. Additionally, significantly lower PNS intensities were needed to elicit peak H-reflex amplitude (Hmax) for long-interval facilitation compared to unconditioned. These findings suggest that the influence of descending corticomotor pathways, particularly those mediating long-interval facilitation, contribute to changing the recruitment gain of the motor neuron pool, and can inform future methodological protocols for TMS-conditioning of H-reflexes. By characterizing and inducing short-term plasticity in circuitry mediating short- and long-interval TMS-conditioning of H-reflex amplitudes, future studies can investigate supraspinal and spinal circuit contributions to abnormal motor control, as well as develop novel therapeutic targets for neuromodulation.

Mechanism of Hsp70 specialized interactions in protein translocation and the unfolded protein response.

Hsp70 chaperones interact with substrate proteins in a coordinated fashion that is regulated by nucleotides and enhanced by assisting cochaperones. There are numerous homologues and isoforms of Hsp70 that participate in a wide variety of cellular functions. This diversity can facilitate adaption or specialization based on particular biological activity and location within the cell. In this review, we highlight two specialized binding partner proteins, Tim44 and IRE1, that interact with Hsp70 at the membrane in order to serve their respective roles in protein translocation and unfolded protein response signalling. Recent mechanistic data suggest analogy in the way the two Hsp70 homologues (BiP and mtHsp70) can bind and release from IRE1 and Tim44 upon substrate engagement. These shared mechanistic features may underlie how Hsp70 interacts with specialized binding partners and may extend our understanding of the mechanistic repertoire that Hsp70 chaperones possess.

UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor.

BiP is a major endoplasmic reticulum (ER) chaperone and is suggested to act as primary sensor in the activation of the unfolded protein response (UPR). How BiP operates as a molecular chaperone and as an ER stress sensor is unknown. Here, by reconstituting components of human UPR, ER stress and BiP chaperone systems, we discover that the interaction of BiP with the luminal domains of UPR proteins IRE1 and PERK switch BiP from its chaperone cycle into an ER stress sensor cycle by preventing the binding of its co-chaperones, with loss of ATPase stimulation. Furthermore, misfolded protein-dependent dissociation of BiP from IRE1 is primed by ATP but not ADP. Our data elucidate a previously unidentified mechanistic cycle of BiP function that explains its ability to act as an Hsp70 chaperone and ER stress sensor.

The role of anatomic pelvic dissection in the successful closure of bladder exstrophy: an aid to success.

INTRODUCTION: Classic bladder exstrophy is one of the rarest congenital anomalies compatible with life. Surgical treatment of bladder exstrophy has progressed, but the goal of surgery remains a successful primary bladder closure. Several factors have been identified to decrease the risk of failed closure, including appropriate use of osteotomy and adequate postoperative immobilization and analgesia. However, the role of the radical anatomic pelvic dissection, including dissection of the urogenital diaphragm fibers, in a successful closure has not yet been extensively explored. OBJECTIVE: The objective of this study was go examine the role of radical anatomic pelvic dissection, including dissection of the urogenital diaphragm fibers, in patients with classic bladder exstrophy. STUDY DESIGN: This was a retrospective study based on an institutional database. METHODS: A retrospective review from an institutional approved database of more than 1,300 patients with epispadias-exstrophy complex was performed. The inclusion criteria included patients with classic bladder exstrophy with at least one failed bladder closure and a reclosure at the authors' institution with a single senior surgeon. Data collection included demographics, clinical variables, and status of urogenital diaphragm fibers. Magnetic resonance imaging (MRI) scans, if available, were reviewed with a pediatric radiologist to identify urogenital diaphragm fibers. RESULTS: From the database, 93 patients met inclusion criteria. Of these patients, 74 had urogenital diaphragm fibers completely intact at the time of repeat closure, whereas 19 patients did not. There was no association with age or gender and status of urogenital diaphragm fibers. There was no association with osteotomy, the type of primary bladder closure, surgeon subspecialty, and the status of the urogenital fibers. Fourteen patients had at least two prior closures; surprisingly, 11 of these repeat closure patients still had intact urogenital fibers even after two prior closures. DISCUSSION: The recent development and application of 3D MRI-guided pelvic dissection in a large group of patients led the authors to investigate whether adequate pelvic floor dissection had been accomplished at primary or secondary closure. Several patients had MRI scans performed before repeat closure in which the urogenital diaphragm fibers were identified to be intact on imaging; this was corroborated with surgical findings. Approximately 80% of patients had their urogenital diaphragm fibers completely intact and, therefore, did not have an adequate pelvic dissection during their primary or secondary bladder closure, putting the success of their previous closures at risk. CONCLUSION: Inadequate pelvic diaphragm dissection, defined as intact urogenital diaphragm fibers, demonstrated in a large group of patients with failed exstrophy closure, may be a decisive factor in bladder closure failure. The use of 3D intra-operative image guidance may aid in a safer and more successful pelvic dissection.

Impact of pelvic immobilization techniques on the outcomes of primary and secondary closures of classic bladder exstrophy.

INTRODUCTION: A potential determinant of successful bladder closures in patients with classic bladder exstrophy (CBE) is the postoperative pelvic immobilization technique. This study investigates the success rates of primary and secondary bladder closures based on various immobilization techniques from a high-volume exstrophy center. METHODS: A prospectively maintained institutional exstrophy-epispadias complex database of 1336 patients was reviewed for patients with CBE who have undergone primary or secondary closures between 1975 and 2018 and subsequently had a known method of pelvic immobilization. Patients were divided into two groups: primary and secondary closures. Associations between closure outcomes and immobilization techniques were determined. RESULTS: A total of 476 patients with primary closures and 101 patients with secondary closures met the inclusion criteria. In total, 343 (72.1%) primary closures were successful. As shown in the table, the success rates of primary closures were highest in patients immobilized with modified Buck's and Bryant's traction (95.0% and 79.3%, respectively) and lowest in those with spica cast (49.6%). A propensity score-adjusted logistic regression (adjusting for osteotomy status, period of closure, location of closure, and closure type) revealed that modified Buck's traction had a 5.60 (95% confidence interval 1.74-23.1, p = 0.008) greater odds of success compared to spica casting during the primary closure. For the secondary closure group, there were 92 (92.1%) successful secondary closures. Success rates were highest in modified Buck's traction (97.3%) and lowest with spica casting (66.7%). DISCUSSION: This study confirms previous findings of better outcomes when patients are immobilized with external fixation and Buck's traction after adjusting for potential confounding factors. Immobilization with modified Buck's or Bryant's traction yielded significantly higher primary closure success rates when compared to spica casting. It is the authors' belief that despite a longer hospital length of stay, external fixation with Buck's traction provides the best chance of a successful closure and, thus, a financially responsible method to care for these children in the postoperative period. CONCLUSIONS: Success rates for primary closures were highest when using modified Buck's traction with external fixation and lowest for spica casts. Similarly, for secondary closures, the best outcomes were achieved using modified Buck's traction with external fixation and the lowest success rates were associated with spica casts.

Structure and Molecular Mechanism of ER Stress Signaling by the Unfolded Protein Response Signal Activator IRE1.

The endoplasmic reticulum (ER) is an important site for protein folding and maturation in eukaryotes. The cellular requirement to synthesize proteins within the ER is matched by its folding capacity. However, the physiological demands or aberrations in folding may result in an imbalance which can lead to the accumulation of misfolded protein, also known as "ER stress." The unfolded protein response (UPR) is a cell-signaling system that readjusts ER folding capacity to restore protein homeostasis. The key UPR signal activator, IRE1, responds to stress by propagating the UPR signal from the ER to the cytosol. Here, we discuss the structural and molecular basis of IRE1 stress signaling, with particular focus on novel mechanistic advances. We draw a comparison between the recently proposed allosteric model for UPR induction and the role of Hsp70 during polypeptide import to the mitochondrial matrix.

The Short-Term Effect of Slope Walking on Soleus H-Reflexes in People with Multiple Sclerosis.

Downslope walking (DSW) causes H-reflex depression in healthy adults, and thus may hold promise for inducing spinal reflex plasticity in people with Multiple Sclerosis (PwMS). The study purpose was to test the hypothesis that DSW will cause acute depression of spinal excitability in PwMS. Soleus H-reflexes were measured in PwMS (n = 18) before and after 20 min of treadmill walking during three visits. Participants walked on a different slope each visit [level: 0% level walking (LW), upslope: +7.5% treadmill walking with an upslope (USW) or downslope: -7.5% (DSW)]. The soleus Hmax/Mmax ratio was used to measure spinal excitability. Heart rate and ratings of perceived exertion (RPE) were measured during walking. DSW induced the largest change in spinal excitability (a 26.7% reduction in soleus Hmax/Mmax (p = 0.001)), although LW also reduced Hmax/Mmax (-5.3%, p = 0.05). Heart rate (p < 0.001) was lowest for DSW, and RPE for DSW did not exceed "Fairly light". DSW evokes short-term spinal plasticity in PwMS, while requiring no greater effort than LW. Our results suggest that PwMS retain the capacity for DSW-induced short-term spinal reflex modulation previously found in healthy adults. These results may provide a foundation for further investigation of long-term effects of DSW on spinal reflex plasticity and functional ability in PwMS.

Predictors and outcomes of perioperative blood transfusions in classic bladder exstrophy repair: A single institution study.

BACKGROUND: Primary bladder closure of classic bladder exstrophy (CBE) is a major operation that occasionally requires intraoperative or postoperative (within 72 h) blood transfusions. OBJECTIVE: This study reported perioperative transfusion rates, risk factors for transfusion, and outcomes from a high-volume exstrophy center in primary bladder closure of CBE patients. STUDY DESIGN: A prospectively maintained, institutional exstrophy-epispadias complex database of 1305 patients was reviewed for primary CBE closures performed at the authors' institution (Johns Hopkins Hospital) between 1993 and 2017. Patient and surgical factors were analyzed to determine transfusion rates, risk factors for transfusions, and outcomes. Patients were subdivided into two groups based upon the time of closure: neonatal and delayed closure. RESULTS: A total of 116 patients had a primary bladder closure during 1993-2017. Seventy-three patients were closed in the neonatal period, and 43 were delayed closures. In total, 64 (55%) patients received perioperative transfusions. No transfusion reactions were observed. Twenty-five transfusions were in the neonatal closure group, yielding a transfusion rate of 34%. In comparison, 39 patients were transfused in the delayed closure group, giving a transfusion rate of 91%. Pelvic osteotomy, delayed bladder closure, higher estimated blood loss (EBL), larger pubic diastasis, and longer operative time were all associated with blood transfusion. In multivariable logistic regression, pelvic osteotomy (OR 5.4; 95% CI 1.3-22.8; P < 0.001), higher EBL-to-weight ratio (OR 1.3; 95% CI 1.1-1.6; P = 0.029), and more recent years of primary closure (OR 1.1; 95% CI 1.0-1.2; P = 0.018) remained independent predictors of receiving a transfusion (Summary Table). No adverse transfusion reactions or complications were observed. DISCUSSION: This was the first study from a single high-volume exstrophy center to explore factors that contribute to perioperative blood transfusions. Pelvic osteotomy as a risk factor was unsurprising, as the osteotomy may bleed both during and immediately after closure. However, it is important to use osteotomy for successful closure, despite the increased transfusion risk. The risks accompanying contemporary transfusions are minimal and osteotomies are imperative for successful bladder closure. CONCLUSIONS: More than half of CBE patients undergoing primary closure at a single institution received perioperative blood transfusions. While there was an association between transfusions and osteotomy, delayed primary closure, larger diastasis, increased operative time, and increased length of stay, only the use of pelvic osteotomy, higher EBL-to-weight ratio, and recent year of closure independently increased the odds of receiving a transfusion on multivariate analysis.

Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1α.

Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). IRE1α is a major UPR transducer, determining cell fate under ER stress. We used an interactome screening to unveil several regulators of the UPR, highlighting the ER chaperone Hsp47 as the major hit. Cellular and biochemical analysis indicated that Hsp47 instigates IRE1α signaling through a physical interaction. Hsp47 directly binds to the ER luminal domain of IRE1α with high affinity, displacing the negative regulator BiP from the complex to facilitate IRE1α oligomerization. The regulation of IRE1α signaling by Hsp47 is evolutionarily conserved as validated using fly and mouse models of ER stress. Hsp47 deficiency sensitized cells and animals to experimental ER stress, revealing the significance of Hsp47 to global proteostasis maintenance. We conclude that Hsp47 adjusts IRE1α signaling by fine-tuning the threshold to engage an adaptive UPR.

Longer Duration of Downslope Treadmill Walking Induces Depression of H-Reflexes Measured during Standing and Walking.

OBJECTIVES: The Hoffman-reflex (H-reflex) is an electrophysiological technique used to evaluate the excitability of the monosynaptic spinal reflex arc. In individuals with upper motor neuron lesions who show elevated spinal excitability, a depression of spinal excitability may indicate adaptive spinal plasticity. Downslope walking (DSW), an exercise intervention comprising repetitive eccentric muscle activity, has been shown to induce depression of soleus H-reflex amplitudes while seated, however, the dose-response time-course of H-reflex modulation during DSW has not been characterized. The objectives of this study were twofold: (1) to evaluate DSW-induced soleus H-reflex depression in the standing posture and during walking, and (2) to investigate the effect of walking duration (20 minutes and 40 minutes) of DSW (-15% decline) on soleus H-reflexes, (with level walking (LW) as a control intervention). METHODS: Soleus H-reflexes were collected Pre, Post-20 minutes, and Post-40 minutes of walking in the standing position; and H-reflexes were also measured at 4 different time points during the terminal stance phase of walking. RESULTS: Our results showed that soleus H-reflexes evaluated in standing showed a greater % depression after DSW compared to LW, with a statistical trend for greater depression with longer durations (40-minutes). H-reflexes measured during walking showed greater depression after 40 minutes of walking compared to 20- or 30-minutes for both DSW and LW. CONCLUSIONS: Longer duration treadmill walking (40-minutes) may induce a greater acute depressive effect on soleus H-reflex excitability compared to shorter durations (20-minutes) of treadmill walking. Future work will investigate the potential for DSW as a gait training intervention in people with upper motor neuron lesions such as multiple sclerosis and stroke.

Changes in prostate cancer detection rate of MRI-TRUS fusion vs systematic biopsy over time: evidence of a learning curve.

BACKGROUND: To determine the effect of urologist and radiologist learning curves and changes in MRI-TRUS fusion platform during 9 years of NCI's experience with multiparametric magnetic resonance imaging (mpMRI)/TRUS fusion biopsy. METHODS: A prospectively maintained database of patients undergoing mpMRI followed by fusion biopsy (Fbx) and systematic biopsy (Sbx) from 2007 to 2016 was reviewed. The patients were stratified based on the timing of first biopsy. Cohort 1 (7/2007-12/2010) accounted for learning curve. Cohort 2 (1/2011-5/2013) and cohort 3 (5/2013-4/2016) included patients biopsied prior to and after debut of a new software platform, respectively. Clinically significant (CS) disease was defined as Gleason 7 (3+4) or higher. McNemar's test compared cancer detection rates (CDRs) of Sbx and Fbx between time periods. RESULTS: 1528 patients were included in the study with 230, 537 and 761 patients included in three respective cohorts. Median age (interquartile range) was 61.0 (±9.0), 62.0 (±7.3), and 64.0 (±11.0) years in three cohorts, respectively (P<0.001). Fbx and Sbx had comparable CS CDR in cohort 1 (24.8 vs 22.2%, P=0.377). Fbx detected significantly more CS disease compared to Sbx in the following two periods (cohort 2: 31.5 vs 25.0%, P=0.001; cohort 3: 36.4 vs 30.3%, P<0.001) and detected significantly less low risk disease in the same period (cohort 2: 14.5 vs 19.6%, P<0.001; cohort 3: 12.6 vs 16.7%, P<0.001). Even after multivariate adjustment with age, PSA, race, clinical stage and MRI suspicion score, Fbx CS cancer detection increased in successive cohorts (cohort 2: OR 2.23, P=0.043; cohort 3: OR 2.92, P=0.007). CONCLUSIONS: In the past 9 years, there has been significant improvement in the accuracy of Fbx. Our results show that after an early learning period, Fbx detected higher rates of CS cancer and lower rates of clinically insignificant cancer than Sbx. Software advances allowed for even greater detection of CS disease.

Multiparametric MRI/ultrasound fusion-guided biopsy decreases detection of indolent cancer in African-American men.

BACKGROUND: Analysis of systematic 12-core biopsies (SBx) has shown that African-American (AA) men tend to harbor higher risk prostate cancer (PCa) at presentation relative to other races. Multiparametric magnetic resonance imaging (mpMRI) and MRI-ultrasound fusion-guided biopsy (FBx) have been shown to diagnose more intermediate- and high-risk PCa in the general population; however, the efficacy in AA remains largely uncharacterized. We aim to evaluate the utility of FBx in an AA patient cohort. METHODS: Men suspected of PCa underwent an mpMRI and FBx with concurrent SBx from 2007 to 2015 in this institutional review board-approved prospective cohort study. Patient demographics, imaging and fusion biopsy variables were collected. χ2, Mann-Whitney U-test and McNemar's tests were performed to compare proportions, means and paired variables, respectively. Clinically significant PCa (CSPCa) was defined as Gleason score ⩾3+4. RESULTS: Fusion biopsy demonstrated exact agreement with SBx risk categories in 64% of AA men. There was no statistically significant difference in the detection of CSPCa between FBx vs SBx (68 vs 62 cases, P=0.36). However, FBx detected 41% fewer cases of clinically insignificant PCa (CIPCa) compared with SBx (FBx 30 vs SBx 51 cases, P=0.0004). The combined FBx/SBx biopsy approach detected significantly more cases of CSPCa (FBx/SBx 80 vs SBx 62 cases, P=0.004) while detecting comparable number of cases of CIPCa (FBx/SBx 45 vs SBx 51 cases, P=0.37) compared with SBx alone. FBx/SBx also detected more CSPCa in patients with a history of prior negative SBx (FBx/SBx 28 vs 19 cases, P=0.003). CONCLUSIONS: FBx when used in combination with SBx detected more cases of CSPCa while not significantly increasing the diagnosis of CIPCa in AA men. Future multicenter studies will be needed to validate ultimately the clinical implications of FBx in AA patients.

The prostate cancer prevention trial risk calculator 2.0 performs equally for standard biopsy and MRI/US fusion-guided biopsy.

BACKGROUND: The Prostate Cancer Prevention Trial Risk Calculator 2.0 (PCPTRC) is a widely used risk-based calculator used to assess a man's risk of prostate cancer (PCa) before biopsy. This risk calculator was created from data of a patient cohort undergoing a 6-core sextant biopsy, and subsequently validated in men undergoing 12-core systematic biopsy (SBx). The accuracy of the PCPTRC has not been studied in patients undergoing magnetic resonance imaging/ultrasound (MRI/US) fusion-guided biopsy (FBx). We sought to assess the performance of the PCPTRC for straitifying PCa risk in a FBx cohort. METHODS: A review of a prospective cohort undergoing MRI and FBx/SBx was conducted. Data from consecutive FBx/SBx were collected between August 2007 and February 2014, and PCPTRC scores using the PCPTRC2.0R-code were calculated. The risk of positive biopsy and high-grade cancer (Gleason ⩾7) on biopsy was calculated and compared with overall and high-grade cancer detection rates (CDRs). Receiver operating characteristic curves were generated and the areas under the curves (AUCs) were compared using DeLong's test. RESULTS: Of 595 men included in the study, PCa was detected in 39% (232) by SBx compared with 48% (287) on combined FBx/SBx biopsy. The PCPTRC AUCs for the CDR were similar (P=0.70) for SBx (0.69) and combined biopsy (0.70). For high-grade disease, AUCs for SBx (0.71) and combined biopsy (0.70) were slightly higher, but were not statistically different (P=0.55). CONCLUSIONS: In an MRI-screened population of men undergoing FBx, PCPTRC continues to represent a practical method of accurately stratifying PCa risk.

Prevalence of Psychiatric Disorders among Female Juvenile Offenders.

Inmates of Juvenile Developmental Centers are the special group of youth population who are in conflict with law. They are vulnerable to psychiatric illness. The objective of this study was to see the prevalence and type of psychiatric disorders in institutionalized female juvenile offenders and non-offenders of same age, sex and socioeconomic group in the community. The association of mental disorders was examined in 43 female inmates of Juvenile Development Centers and 43 randomly selected comparison subjects in community. One stage-structured assessment of psychopathology was carried out by using a structured and valid Bangla version of the Development and Well-Being Assessment (DAWBA). Development and Well-Being Assessment generated psychiatric diagnosis was assigned based on ICD-10 diagnostic criteria for research. The result revealed that, of those who were in conflict with law, 93% had mental disorder, whereas 14% of non-offenders had psychiatric disorder. Among the offenders with psychiatric disorders, most of them (32.6%) suffered from Major Depressive Disorder (MDD), followed by combined MDD & Post Traumatic Stress Disorder (PTSD). On the other hand, among the non-offenders with psychiatric disorder 9.3% suffered from MDD. It can be concluded that considerable psychiatric disorders are prevalent among the female juvenile offenders with comparison to non-offenders. Broad-based replication study could confirm these findings.

Compounds Triggering ER Stress Exert Anti-Melanoma Effects and Overcome BRAF Inhibitor Resistance.

We have discovered and developed a series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all melanoma cells tested, including cells isolated from patients and cells that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic, and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases ER stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms.