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The surgeon involved in the management of breast disease must work as part of an effective multidisciplinary team. The surgeon must work with all team members communicating effectively and working together. Histopathology provides diagnostic, prognostic and predictive information. The surgeon must understand the implications of the histopathology report for effective patient management. Improvements in core biopsy techniques have provided additional information resulting in lower open biopsy rates and improved preoperative diagnostic rates for facilitating surgical planning. Assessment of margin status, lymph node status and prognostication are continually evolving and shaping surgical practice towards less surgical intervention in the field of breast disease. Molecular testing is becoming an increasingly important aspect of breast cancer management in the era of precision medicine. [ABSTRACT FROM AUTHOR]

It is important to determine whether anthracycline-containing regimens or taxane-containing regimens are more effective in individual patients. The present study compared the efficacy of six cycles of docetaxel and cyclophosphamide (TC6) with that of three cycles of 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel (FEC-D) in Japanese patients with hormone receptor (HR)-negative breast cancer (BC) to identify subtypes requiring anthracycline treatment. The study included 103 patients with operable HR-negative BC. Of these patients 53 received FEC-D and 50 received TC6. The primary endpoint was pathological complete response (pCR). The secondary endpoints were safety, breast-conserving surgery, disease-free survival (DFS) and overall survival (OS). The predictive factors for each regimen were evaluated. Of the 103 patients, 97 completed the study (FEC-D, 50 patients; TC6, 47 patients). The pCR rate was higher with FEC-D (36%) than with TC6 (25.5%); however, the difference was not significant (P = 0.265). TC6 was safer than FEC-D, as the adverse events with docetaxel in the FEC-D regimen were similar to those with the TC6 regimen. Among patients with basal BC, the pCR rate was significantly higher with FEC-D (42.9%) than with TC6 (13.6%; P = 0.033). Among patients with triple-negative breast cancer (TNBC), the DFS and OS were significantly better with FEC-D than with TC6 (P = 0.016 and P = 0.034, respectively). TC6 was not as effective as FEC-D for treating HR-negative BC, as TC6 was not sufficient to treat TNBC, particularly the basal subtype. Our findings suggest that anthracyclines are better treatment options than taxanes for basal BC. • The pCR rate was higher with FEC-D than with TC6 (P = 0.265). • For basal BC, the pCR rate was higher with FEC-D than with TC6 (P = 0.033). • For TNBC, DFS and OS were better with FEC-D than with TC6 (P = 0.016 and P = 0.034). [ABSTRACT FROM AUTHOR]

Individuality has to do with our differences and similitudes, our phenotype and genotype characteristics that make us unique in some ways, and common in others. In this study we applied linear and non-linear quantitative description of the EEG signal of 8 subjects in closed eyes, basal conditions, three times at a day (at 10:00, 13:00, and 16:00 hrs. UTC -04:00 Santiago), to provide evidence that allows us to narrow the boundaries of intra and inter-individual differences in the behavior of the oscillatory electrical signal of the brain. We applied two versions of Hurst exponent estimator of persistence/anti-persistence of the brain signal, and a Spearman R inter-correlation analysis between pairs of EEG channels to quantify and allocate the magnitude of highly correlated pairs of electrodes as an indicator of enhanced brain synchrony. Results showed differences and patterns in laterality/symmetry associated with magnitude, self-organized long-memory processes; and brain synchrony. [ABSTRACT FROM AUTHOR]

The study presents a frequency domain, instead of a relative power intensity comparison framework domain, that evaluates the degree of anxiety and stress brain network activated in high beta oscillation (22-30 Hz), during a resting, EC basal condition of EEG recording. The parameter measured served as an evaluator of the brain spontaneous, self-generated, global de-synchronizing, workload endogenous attractors that displace the EEG oscillatory dynamics toward free energy-consuming processing loops. The distinction of the high beta EEG waves as related with stress and anxiety, together with an approach based primarily on the inter-channel frequency correlation, rather than only the power activation of the frequency beta range, allowed us to supplement with new finding and ways to evaluate the impact of self-generated processing attractors that kept our brain apart from natural tendency to re-synchronize, save and reorganize energy. [ABSTRACT FROM AUTHOR]

Meningiomas are the second commonest intracranial tumors in many places worldwide. They are rare in the pediatric age group, however, and most studies have been able to document only a few patients. Meningiomas in pediatric patients have also been shown to behave differently from those in the adult population. This study was done to examine histologic types of meningiomas seen in pediatric patients from a predominantly African population using the 2016 World Health Organization (WHO) grading system for intracranial tumors. Data from the operating logs of patients and histology reports of the samples sent to the pathology department during the study period were extracted. The data obtained were the age, sex, location of the intracranial tumor, histologic diagnosis, WHO grade, and tumor recurrence. Nine pediatric age patients were found among the 166 surgically excised meningiomas received at the pathology department in our institution over a 19-year period. The age range was from 8 months to 17 years. There was a male-to-female ratio of 1:2 with a female predominance. Six tumors were basally located. All tumors were WHO grade I with transitional meningiomas being the commonest followed by meningothelial. There was no history of recurrence in any of the tumors after complete surgical excisions. Our study showed the rarity of meningiomas in the study population, and there was a predominance of basally located tumors. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the glycaemic control of combination therapy with basal insulin and liraglutide, and to explore the factors predictive of efficacy in patients with type 2 diabetes when switched from longstanding basal-bolus insulin therapy.Methods: We studied 41 patients who switched from basal-bolus insulin therapy of more than 3 years to basal insulin/liraglutide combination therapy. Glycaemic control was evaluated at 6 months after switching therapy and used to subdivide the patients into good-responders (HbA1c <7.0% or 1.0% decrease) and poor-responders (the rest of participants). To evaluate the glucose-dependent insulin/glucagon responses without/with liraglutide, a 75-g oral glucose tolerance test (OGTT) was performed twice, before (1st-OGTT) and 2-days after (2nd-OGTT) liraglutide administration.Results: Twenty-eight patients (68.3%) were identified as good-responders. No differences were found in baseline characteristics including insulin/glucagon responses during 1st-OGTT between the groups. 2nd-OGTT revealed that paradoxical hyperglucagonemia were significantly improved in both groups, but significant increases in insulin secretory response were observed only in good-responders. Logistic regression analyses revealed that the improvement of the insulin-response during 2nd-OGTT compared to that during 1st-OGTT is associated with the good-responder.Conclusions: Enhancement of glucose-dependent insulin-response under liraglutide administration is a potential predictor of long-term glycaemic control after switching the therapies. [ABSTRACT FROM AUTHOR]

Basal ganglia circuits are organized to selected desired actions and to inhibit potentially competing unwanted actions. This is accomplished through a complex circuitry that is modified through development and learning. Mechanisms of neural plasticity underlying these modifications are increasingly understood, but new mechanisms continue to be discovered. Dystonia, a movement disorder characterized by involuntary muscle contractions that cause abnormal postures and movements. Emerging evidence points to important links between mechanisms of plasticity and the manifestations of dystonia. Investigation of these mechanisms has improved understanding of the action of currently used medication and is informing the development of new treatments. [ABSTRACT FROM AUTHOR]

Background The pathophysiological hypothesis underlying tic disorders in Tourette syndrome (TS) is that basal ganglia are not capable of properly filtering cortical information, leading patients with difficulties in inhibiting unwanted behaviors or impulses. One of the main challenges for furthering such a hypothesis is to find appropriate animal models summarizing some aspects of the disease. Methods It has been established for more than 25 years in rodents that the prototypical serotonin (5-HT) agonist meta -chlorophenylpiperazine (m-CPP) elicits purposeless oral movements including chewing behavior. These bouts of oral movements, originally thought to mimic human oral dyskinesia consequent to long-term administration of antipsychotic drugs or parkinsonian tremor, could correspond to an undefined form of tics. Here, we describe the nature of the purposeless oral movements triggered by m-CPP and other agonists which could be associated with obsessive compulsive disorders. We report the pharmacology of this response with a focus on the 5-HT 2C receptor subtype and the degree to which the dopaminergic and cholinergic systems are involved. The orofacial dyskinetic effects are related to the action of these compounds in associative/limbic territories of the basal ganglia, rather than sensorimotor ones, as expected from the human disease. Conclusion In spite of the low translational value of these oral movements, the neurobiological analysis of these oral movements could help to a better understanding of the pathophysiology of tics and compulsive disorders often cormorbid with TS. [ABSTRACT FROM AUTHOR]

Background: Molecular classification of bladder cancer has been increasingly proposed as a potential tool to predict clinical outcomes and responses to chemotherapy. Here we focused on mechanistic target of rapamycin (mTOR) inhibition as a chemotherapeutic strategy and characterized the expression profile of mTOR signaling targets in representative bladder cancer cell lines from basal, luminal, and either basal/luminal ("non-type") molecular subtypes.Materials and Methods: Protein and mRNA expression of mTOR signaling components from representative luminal (RT4 and RT112), basal (SCaBER and 5637), and nontype (T24 and J82) bladder cancer cell line subtypes were determined by Western blot and database mining analysis of the Cancer Cell Line Encyclopedia. Cell viability following treatment with either, Torin-2 or KU-0063794, 2 dual mTOR complex 1/2 inhibitors, was determined by MTT assay. Immunoblot analysis of cells treated with Torin-2 or KU-0063794 was performed to determine the effects of mTOR inhibition on expression and phosphorylation status of mTOR signaling components, Akt, 4E-BP1, and ribosomal protein S6.Results: Molecular subtypes of bladder cancer cell lines each exhibited a distinct pattern of expression of mTOR-associated genes and baseline phosphorylation level of Akt and 4E-BP1. Cells with low levels of Akt Ser-473 phosphorylation were more resistant to the cytotoxic effects of mTOR inhibition with Torin-2, but not KU-0063794. Exposure to Torin-2 and KU-0063794 both potently and rapidly inhibited phosphorylation of Akt Ser-473 and Thr-308, and 4E-BP1 T37/46 in cell lines that included basal and nontype subtypes.Conclusions: Differential gene expression and protein activity associated with mTOR signaling is observed among bladder cancer cell lines stratified into basal, luminal, and nontype subtypes. Urothelial carcinomas characterized by high baseline Akt Ser-473 phosphorylation may be best suited for targeted mTOR therapies. [ABSTRACT FROM AUTHOR]

Summary Sporadic mitochondrial DNA mutations serve as clonal marks providing access to the identity and lineage potential of stem cells within human tissues. By combining quantitative clonal mapping with 3D reconstruction of adult human prostates, we show that multipotent basal stem cells, confined to discrete niches in juxta-urethral ducts, generate bipotent basal progenitors in directed epithelial migration streams. Basal progenitors are then dispersed throughout the entire glandular network, dividing and differentiating to replenish the loss of apoptotic luminal cells. Rare lineage-restricted luminal stem cells, and their progeny, are confined to proximal ducts and provide only minor contribution to epithelial homeostasis. In situ cell capture from clonal maps identified delta homolog 1 (DLK1) enrichment of basal stem cells, which was validated in functional spheroid assays. This study establishes significant insights into niche organization and function of prostate stem and progenitor cells, with implications for disease. [ABSTRACT FROM AUTHOR]

Aims: To describe patterns of home insulin dose adjustments for non-surgical, non-critically ill patients at admission and to describe associations between these adjustments and inpatient glycemic control.Methods: Hospital records of non-critically ill patients treated with basal insulin prior to admission were identified. After exclusion of records in which a confounding factor influencing insulin dosing was present, 258 patient-admissions over a 3-year time period were included. Multivariate logistic regression was used to analyze the association between adjustments to home insulin total daily dose (TDD) and inpatient glycemic control within the first 48h, adjusting for relevant confounders.Results: On hospital days 1 (HD1) and 2 (HD2), the home insulin TDD was reduced by 43.5% and 23.9%, respectively. Reductions in the home TDD ranging from 10% to 50% were not associated with normoglycemia or hyperglycemia, whereas increases ranging from 10% to 50% were associated with 2-5-fold increased odds of hyperglycemia. For patients with home insulin TDD ≥0.4units/kg/day, a weight-based dose of 0.4-0.6units/kg/day was associated with significantly higher odds of normoglycemia on HD2 (OR 3.99; 95% CI 1.42-11.21) compared to lower doses.Conclusions: Compared to less aggressive increases, home insulin dose increases ranging from 10% to 50% were associated with greater odds of hyperglycemia without increased odds of hypoglycemia during early hospitalization. Weight-based insulin dosing may be a preferred strategy for glycemic control among patients whose home TDD is ≥0.4units/kg/day. [ABSTRACT FROM AUTHOR]

Background: Basal insulin supported oral therapy (BOT) can greatly improve glycaemic control; however, it may not be an optimal treatment for every patient. The identification of patient-related characteristics that may predict a switch of the treatment strategy away from BOT after originally initiating it, would be useful when deciding on treatment strategies clinically.Methods: Data from the German DIabetes Versorgungs-Evaluation (DIVE) registry were analysed for patients treated with BOT for at least 3months. BOT discontinuation was defined as the cessation of oral therapy, of insulin therapy, or the addition of short-acting insulin. Risk quantification for demographics, glycaemic control, and treatment characteristics of patients were based on Cox proportional hazards regression.Results: BOT discontinuation occurred in 2021 patients (35.7%) of the 5663 that fulfilled the inclusion criteria for the study. Of these, 46.7% discontinued oral therapy, 32.7% discontinued insulin, and 20.6% had short-acting insulin added to their treatment. Multivariate analysis revealed that higher body mass index (BMI; hazard ratio, HR: 1.012; 95% CI: 1.001-1.023; p=0.029), shorter diabetes duration (HR: 0.982; 95% CI: 0.976-0.989; p<0.001), and higher HbA1c level (HR: 1.102; 95% CI: 1.022-1.188; p=0.011) were associated with BOT discontinuation.Conclusions: Identification of factors that may be predictive of a discontinuation of BOT could be highly useful in a clinical setting when assessing the most appropriate treatment strategy for type 2 diabetes patients. [ABSTRACT FROM AUTHOR]

Background Gene expression profiling (GEP) suggests there are three subtypes of muscle-invasive urothelial cancer (UC): basal, which has the worst prognosis; p53-like; and luminal. We hypothesized that GEP of transurethral resection (TUR) and cystectomy specimens would predict subtypes that could benefit from chemotherapy. Objective To explore clinical outcomes for patients treated with dose-dense (DD) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and bevacizumab (B) and the impact of UC subtype. Design, setting, and participants Sixty patients enrolled in a neoadjuvant trial of four cycles of DDMVAC + B between 2007 and 2010. TUR and cystectomy specimens for GEP were available from 38 and 23 patients, respectively, and from an additional confirmation cohort of 49 patients treated with perioperative MVAC. Outcome measurements and statistical analysis Relationships with outcomes were analyzed using multivariable Cox regression and log-rank tests. Results and limitations Chemotherapy was active, with pT0N0 and ≤pT1N0 downstaging rates of 38% and 53%, respectively, and 5-yr overall survival (OS) of 63%. Bevacizumab had no appreciable impact on outcomes. Basal tumors had improved survival compared to luminal and p53-like tumors (5-yr OS 91%, 73%, and 36%, log-rank p = 0.015), with similar findings on multivariate analysis. Bone metastases within 2 yr were exclusively associated with the p53-like subtype (p53-like 100%, luminal 0%, basal 0%; p ≤ 0.001). Tumors enriched with the p53-like subtype at cystectomy suggested chemoresistance for this subtype. A separate cohort treated with perioperative MVAC confirmed the UC subtype survival benefit (5-yr OS 77% for basal, 56% for luminal, and 56% for p53-like; p = 0.021). Limitations include the small number of pretreatment specimens with sufficient tissue for GEP. Conclusion GEP was predictive of clinical UC outcomes. The basal subtype was associated with better survival, and the p53-like subtype was associated with bone metastases and chemoresistant disease. Patient summary We can no longer think of urothelial cancer as a single disease. Gene expression profiling identifies subtypes of urothelial cancer that differ in their natural history and sensitivity to chemotherapy. [ABSTRACT FROM AUTHOR]

We characterize invasive urothelial carcinoma (UC) exhibiting urothelial basal cell immunohistochemical markers. Consecutive invasive UCs were immunostained with CK20 and urothelial basal cell markers, cytokeratin 5 (CK5)/CD44. Immunostaining for CK5 and CD44 was scored as follows: positive for staining of more than 25% thickness of the epithelial nest or epithelium and low for lesser immunoreactivity. Invasive urothelial carcinoma (UC) exhibiting positive CK5/CD44 staining was designated as basal-like UC (BUC). In this study, of 251 invasive UC (pT1 in 57% and pT2-4 in 43%), BUC accounted for 40% of cases (accounting for most pT2-4 UC) and often presented as non-papillary UC without previous history of UC. In addition, BUC exhibited uniform nuclei with lesser degree of atypia than non BUC and decreased or negative cytokeratin 20 reactivity. Nested and microcystic variants of UC immunohistochemically stained as BUCs. Invasive non-BUCs were often papillary with marked cytologic atypia and pleomorphism, and accounted for most pT1 UC. The rates of perivesical invasion, lymph node and distant metastases were higher for BUC than non-BUC. All nine cases with absent/minimal residual in situ UC in 102 radical cystectomy specimens were from invasive non-BUC. BUC is distinguished from non-BUC due to this aggressive behavior, distinct immunohistochemical profile, and predominant non-papillary architecture. Our findings are consistent with recent studies identifying a subtype of muscle-invasive UC with molecular expression of basal cell and luminal cell molecular profiles. Our study further supports categorizing invasive UCs into these subtypes with different biological behaviors, possibly contributing to better therapeutic strategies. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Breast cancer is a heterogeneous disease. Immunohistochemistry has given rise to triple-negative carcinoma (TNC). Concomitantly, biological origins of neoplasia and its heterogeneity has been strongly debated in cancer stem cells (CSC) theme. This study investigates the prevalence of basal (BCC) and penta-negative carcinomas (5NC) in TNC and establishes associations with CSC (CD44CD24). Materials and methods: 94 TNC were tested for CK5/6, HER1, CD44 and CD24, evaluated by a simple immunohistochemistry score and correlated with clinicopathological and survival data. Results: BCC had higher tumor grades than 5NC (p =0.004). CD44 negativity (p =0.007) and CD44−CD24+ phenotype (p =0.013) were associated with less vascular invasion amongst TNC. CD44 expression was associated with BCC (p =0.007). CD44−CD24−/low phenotype was associated with 5NC. None of the variables were associated with clinical outcome. Conclusion: BCC and 5NC are closely related tumor subtypes. CD44−CD24−/low phenotype was associated with 5NC and CD44−CD24+ phenotype was associated with vascular invasion. These results require histogenetic confirmation in larger studies. [Copyright &y& Elsevier]

There are many surgical procedures that provide pain relief and improve function for trapeziometacarpal (TM) arthritis. The aim of this article is to review the history of surgical treatment of thumb basal joint arthritis and to discuss some of the recent advances based on evolving technology. Our preferred treatment is described, and explanation provided for why we have avoided the temptation to change to the "latest and greatest" treatment for this condition. [ABSTRACT FROM AUTHOR]

Background Basal-like and triple-negative breast tumours encompass an important clinical subgroup and biomarkers that can prognostically stratify these patients are required. Materials and methods We investigated two breast cancer tissue microarrays for the expression of calpain-1, calpain-2 and calpastatin using immunohistochemistry. The first microarray was comprised of invasive tumours from 1371 unselected patients, and the verification microarray was comprised of invasive tumours from 387 oestrogen receptor (ER)-negative patients. Results The calpain system contains a number of proteases and an endogenous inhibitor, calpastatin. Calpain activity is implicated in important cellular processes including cytoskeletal remodelling, apoptosis and survival. Our results show that the expression of calpastatin and calpain-1 are significantly associated with various clinicopathological criteria including tumour grade and ER expression. High expression of calpain-2 in basal-like or triple-negative disease was associated with adverse breast cancer-specific survival (P = 0.003 and <0.001, respectively) and was verified in an independent cohort of patients. Interestingly, those patients with basal-like or triple-negative disease with a low level of calpain-2 expression had similar breast cancer-specific survival to non-basal- or receptor- (oestrogen, progesterone or human epidermal growth factor receptor 2 (HER2)) positive disease. Conclusions Expression of the large catalytic subunit of m-calpain (calpain-2) is significantly associated with clinical outcome of patients with triple-negative and basal-like disease. [ABSTRACT FROM PUBLISHER]

Purpose: To determine whether breast cancer subtype is associated with patterns of ipsilateral breast tumor recurrence (IBTR), either true recurrence (TR) or elsewhere local recurrence (ELR), among women with pT1–T2 invasive breast cancer (IBC) who receive breast-conserving therapy (BCT). Methods and Materials: From Jan 1998 to Dec 2003, 1,223 women with pT1–T2N0-3 IBC were treated with BCT (lumpectomy plus whole-breast radiation). Ninety percent of patients received adjuvant systemic therapy, but none received trastuzumab. Biologic cancer subtypes were approximated by determining estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), and human epidermal growth factor receptor-2-positive (HER-2+) expression, classified as luminal A (ER+ or PR+ and HER-2 negative [HER-2−]), luminal B (ER+ or PR+ and HER-2+), HER-2 (ER− and PR− and HER-2+), and basal (ER− and PR− and HER-2− ) subtypes. Imaging, pathology, and operative reports were reviewed by two physicians independently, including an attending breast radiologist. Readers were blinded to subtype and outcome. TR was defined as IBTR within the same quadrant and within 3 cm of the primary tumor. All others were defined as ELR. Results: At a median follow-up of 70 months, 24 patients developed IBTR (5-year cumulative incidence of 1.6%), including 15 TR and 9 ELR patients. At 5 years, basal (4.4%) and HER-2 (9%) subtypes had a significantly higher incidence of TR than luminal B (1.2%) and luminal A (0.2%) subtypes (p < 0.0001). On multivariate analysis, basal subtype (hazard ratio [HR], 4.8, p = 0.01), younger age at diagnosis (HR, 0.97; p = 0.05), and increasing tumor size (HR, 2.1; p = 0.04) were independent predictors of TR. Only younger age (HR, 0.95; p = 0.01) significantly predicted for ELR. Conclusions: Basal and HER-2 subtypes are significantly associated with higher rates of TR among women with pT1–T2 IBC after BCT. Younger age predicts for both TR and ELR. Strategies to reduce TR in basal breast cancers, such as increased boost doses, concomitant radiation and chemotherapy, or targeted therapy agents, should be explored. [ABSTRACT FROM AUTHOR]

Purpose: The goal of this study was to evaluate the 4-year minimum (5.5-y average) results of trapeziectomy and ligament reconstruction using a modified Thompson technique with the abductor pollicis longus tendon for the primary treatment of advanced-stage basal joint arthritis (Eaton stages III and IV). Methods: We evaluated 25 thumbs in 18 patients after ligament reconstruction arthroplasty for surgical treatment of advanced thumb basal joint arthritis. Treatment consisted of piecemeal excision of the entire trapezium, ligament reconstruction and interposition using the abductor pollicis longus tendon, and 8 weeks of K-wire immobilization of the thumb metacarpal. We evaluated range of motion, lateral pinch, tip pinch, grip strength, and outcomes questionnaires including the Arthritis Impact Measurement Scales 2 Short Form before and at an average of 5.5 years after surgery. Results: Seventeen of 18 patients reported excellent or good relief of pain and were satisfied with their operation, and all of the patients would have the operation again. Of the 25 thumbs, 24 adducted fully into the plane of the palm and opposed to the fifth metacarpal head. Preoperative and postoperative strength comparisons demonstrated an average increase in grip, key pinch, and tip pinch strength of 14%, 12%, and 6%, respectively. The outcomes data demonstrated noteworthy improvement in writing, buttoning a shirt, turning a key/lock, and arthritis pain categories. Conclusions: This technique restored a stable, pain-free thumb that yielded excellent strength and motion at an average of 5.5 years after the procedure. Compared with published reports of techniques that use hematoma distraction or harvest of all or part of the flexor carpi radialis tendon, this modified Thompson technique has similar pain relief, satisfaction, and motion but had less improvement in strength, which might have resulted from differences in the studied samples. Type of study/level of evidence: Therapeutic IV. [ABSTRACT FROM AUTHOR]

Abstract: Triple-negative breast cancer (TNBC) accounts for approximately 15% of breast cancer diagnoses, and exhibits substantial overlap with basal-type and BRCA1-positive breast cancer. In recent years, a greater understanding of the biology of this disease has led to the development of numerous and varied therapeutic approaches. Neoadjuvant trials using conventional cytotoxic agents such as cisplatin have demonstrated TNBC to be a relatively chemo-sensitive disease. In the current review, focus is directed towards novel targeted strategies for TNBC. Recent trials have shown the poly(ADP-ribosyl)ation polymerase (PARP) inhibitors BSI-201 and olaparib to be highly effective in TNBC and BRCA1/2-positive disease, respectively. Efforts to assess the role of antiangiogenic agents such as bevacizumab and sunitinib in TNBC are ongoing. Finally, preclinical studies provide a signal of potential activity with use of heat shock protein 90 (Hsp90) and Src inhibitors in this breast cancer subtype. [Copyright &y& Elsevier]

Abstract: Chondroitin sulfate proteoglycans (CSPGs) are a key structural component of the brain extracellular matrix. They are involved in critical neurodevelopmental functions and are one of the main components of pericellular aggregates known as perineuronal nets. As a step toward investigating their functional and pathophysiological roles in the human amygdala, we assessed the pattern of CSPG expression in the normal human amygdala using wisteria floribunda agglutinin (WFA) lectin histochemistry. Total numbers of WFA-labeled elements were measured in the lateral (LN), basal (BN), accessory basal (ABN) and cortical (CO) nuclei of the amygdala from 15 normal adult human subjects. For interspecies qualitative comparison, we also investigated the pattern of WFA labeling in the amygdala of naïve rats (n =32) and rhesus monkeys (Macaca mulatta; n =6). In human amygdala, WFA lectin histochemistry resulted in labeling of perineuronal nets and cells with clear glial morphology, while neurons did not show WFA labeling. Total numbers of WFA-labeled glial cells showed high interindividual variability. These cells aggregated in clusters with a consistent between-subjects spatial distribution. In a subset of human subjects (n =5), dual color fluorescence using an antibody raised against glial fibrillary acidic protein (GFAP) and WFA showed that the majority (93.7%) of WFA-labeled glial cells correspond to astrocytes. In rat and monkey amygdala, WFA histochemistry labeled perineuronal nets, but not glial cells. These results suggest that astrocytes are the main cell type expressing CSPGs in the adult human amygdala. Their highly segregated distribution pattern suggests that these cells serve specialized functions within human amygdalar nuclei. [Copyright &y& Elsevier]

Abstract: Objective: The role of apical versus basal cochlear implant electrode stimulation on central auditory development was examined. We hypothesized that, in children with early onset deafness, auditory development evoked by basal electrode stimulation would differ from that evoked more apically. Methods: Responses of the auditory nerve and brainstem, evoked by an apical and a basal implant electrode, were measured over the first year of cochlear implant use in 50 children with early onset severe to profound deafness who used hearing aids prior to implantation. Results: Responses at initial stimulation were of larger amplitude and shorter latency when evoked by the apical electrode. No significant effects of residual hearing or age were found on initial response amplitudes or latencies. With implant use, responses evoked by both electrodes showed decreases in wave and interwave latencies reflecting decreased neural conduction time through the brainstem. Apical versus basal differences persisted with implant experience with one exception; eIII–eV interlatency differences decreased with implant use. Conclusions: Acute stimulation shows prolongation of basally versus apically evoked auditory nerve and brainstem responses in children with severe to profound deafness. Interwave latencies reflecting neural conduction along the caudal and rostral portions of the brainstem decreased over the first year of implant use. Differences in neural conduction times evoked by apical versus basal electrode stimulation persisted in the caudal but not rostral brainstem. Significance: Activity-dependent changes of the auditory brainstem occur in response to both apical and basal cochlear implant electrode stimulation. [Copyright &y& Elsevier]

Neuroferritinopathy (MIM 606159, also labeled hereditary ferritinopathy and neurodegeneration with brain iron accumulation type 2, NBIA2) is an adult-onset progressive movement disorder caused by mutations in the ferritin light chain gene (FTL1). Four pathogenic mutations in FTL1 have been described to date; 460insA was our original founder mutation in Cumbria, North West England, where it arose before 1800. The same mutation appears to have arisen separately in France. The resulting altered reading frame extends the peptide, disrupting the ferritin dodecahedron structure and causing accumulation of ferritin and iron, primarily in central neurons. A wide range of neurologic symptoms may occur; 50% present with chorea, 43% with limb dystonia, and 7% with Parkinsonian features. The disorder provides a direct link between disordered iron storage and a neurodegenerative disease, opening new avenues for treatment by altering brain iron stores in addition to symptomatic treatments such as local Botulinum toxin and oral anti oxidants. [Copyright &y& Elsevier]

Abstract: Fate maps are essential to understand embryonic development; they provide a background for deducing maps of differential cellular specification in the context of other experimental data and molecular expression patterns. Due to its accessibility, the chick neural plate has been fate-mapped many times, albeit without complete agreement with respect to its shape, extent and fated subdivisions. In this review, we first comment about avian neural plate fate maps reported since the early period of experimental embryology, referring to the different methods followed. We next review a perfected fate-mapping methodology, which recently allowed us rather precise delimitation of the chick neural plate at stages 3d/4. This leads to a general discussion about the apparent border of the neural plate and the prospective main rostrocaudal and longitudinal divisions of the neural tube. [Copyright &y& Elsevier]

Abstract: Establishment of appropriate basal insulin levels is an essential component of intensive insulin therapy. While the existence of a “dawn phenomenon” is widely recognized, the present study sought to establish whether diurnal basal insulin patterns exist in Type-1 diabetes, and whether these patterns vary by age and gender. Participant data was drawn from 322 Type-1 insulin pump users treated at a private diabetes education practice in suburban Philadelphia. All participants completed a battery of fasting tests designed to match basal insulin levels to endogenous glucose production and insulin sensitivity. Analysis of resultant basal patterns revealed significant differences between juvenile (age ≤20) and adult (age >20) basal insulin patterns. The younger group exhibited a more pronounced and sustained night-time peak; the older group exhibiting a briefer and less pronounced early-morning peak. Lower overall basal insulin requirements were found in the youngest (age ≤10) and oldest (age >60) groups. No noteworthy gender differences were found. Results can serve as a guide for clinicians when initiating and fine-tuning patients who utilize basal/bolus insulin therapy. [Copyright &y& Elsevier]

Abstract: A novel controlled release formulation has been developed with PEGylated human insulin encapsulated in PLGA microspheres that produces multi-day release in vivo. The insulin is specifically PEGylated at the amino terminus of the B chain with a relatively low molecular weight PEG (5000 Da). Insulin with this modification retains full biological activity, but has a limited serum half-life, making encapsulation necessary for sustained release beyond a few hours. PEGylated insulin can be co-dissolved with PLGA in methylene chloride and microspheres made by a single o/w emulsion process. Insulin conformation and biological activity are preserved after PEGylation and PLGA encapsulation. The monolithic microspheres have inherently low burst release, an important safety feature for an extended release injectable insulin product. In PBS at 37 °C, formulations with a drug content of approximately 14% show very low (&#60;1%) initial release of insulin over one day and near zero order drug release after a lag of 3–4 days. In animal studies, PEG–insulin microspheres administered subcutaneously as a single injection produced &#60;1% release of insulin in the first day but then lowered the serum glucose levels of diabetic rats to values &#60;200 mg/dL for approximately 9 days. When doses were given at 7-day intervals, steady state drug levels were achieved after only 2 doses. PEG–insulin PLGA microparticles show promise as a once-weekly dosed, sustained release basal insulin formulation. [Copyright &y& Elsevier]

Abstract: Extracellular glutamate levels increase as a consequence of perinatal hypoxia/ischemia, causing the death of neurons and oligodendrocytes. Precursors in the subventricular zone (SVZ) also die following perinatal hypoxia/ischemia; therefore we hypothesized that glutamate would stimulate the death of neural precursors. Here we demonstrate using calcium imaging that SVZ derived neural stem/progenitor cells respond to both ionotropic and metabotropic excitatory amino acids. Therefore, we tested the effects of high levels of glutamate receptor agonists on the proliferation, survival, and differentiation of SVZ derived neural stem/progenitor cells in vitro. We show that high levels of glutamate, up to 1 mM, are not toxic to neural precursor cultures. In fact, stimulation of either the kainate receptor or group 2 metabotropic glutamate receptors (group 2 mGluR) reduces basal levels of apoptosis and increases neural precursor proliferation. Furthermore, group 2 mGluR activation expands the number of multipotent progenitor cells present in these cultures while maintaining equivalent mature cell production. We conclude that the glutamate released following perinatal hypoxia/ischemia may act to acutely promote the proliferation of multipotent precursors in the subventricular zone. [Copyright &y& Elsevier]

Abstract: Targeted therapies for breast cancer reflect the underlying genomic complexity of the disease. These cancers, in turn, are Darwinian constructs, acting much like species undergoing mutational events, and with environmental pressures selecting evolutionary winners and losers. It is therefore reasonable to consider the evolution of targeted biologic therapies in classic evolutionary terms. This paper will examine breast cancer therapeutics in terms of species undergoing adaptational changes as a consequence on mutational events, and will examine the prospects for new therapeutic species. [Copyright &y& Elsevier]

Genomic studies have delineated distinct molecular subgroups of urothelial carcinomas whose prognostic impact extends beyond traditional stage and grade groupings. The ' basal ' subgroup shows increased gene expression levels of KRT5 , KRT6 , and KRT14 and low expression levels of GATA binding protein 3, and is associated with an extremely poor outcome. Identification of this subset is necessary for improved patient management and research on targeted therapies. We aimed to assess the prognostic utility of immunohistochemistry (IHC) for basal markers: cytokeratin 5/6 (CK5/6) and 14 (CK14), and luminal markers: cytokeratin 20 (CK20) and Gata3 in muscle invasive urothelial carcinomas (MIBC). Study was of retrospective design (2014‐2017). All chemotherapy naïve patients of MIBC undergoing radical cystectomy were included. IHC was performed on formalin fixed paraffin-embedded whole tumor sections. Among 40 cases of MIBC included, 45% (18/40) were positive for one or both basal markers, 37.5% (15/40) were positive for one or both luminal markers, while 15% (6/40) were positive for both basal and luminal markers. One case did not express any of the four markers. MIBCs expressing only basal markers presented at an advanced stage with frequent squamous differentiation and showed a trend towards shorter overall survival. Gata3+ MIBCs showed the best outcome irrespective of expression of other markers, while CK14+/Gata3- MIBCs were associated with worst outcomes. Gata3-/CK14- MIBCs showed intermediate survival outcomes. CK5/6, CK20 and p53 expression did not significantly correlate with outcome. IHC for Gata-3 and CK14 stratified MIBC into distinct prognostic subsets. • Loss of Gata3 protein in MIBCs is an independent predictor of poor overall survival. • Cytokeratin-14 positive, Gata3 negative tumors associated with worst outcomes • Cytokeratin 5/6, cytokeratin 20 or p53 did not correlate with survival outcomes. • Combination of Gata3/cytokeratin-14 stratified MIBCs into three prognostic groups. [ABSTRACT FROM AUTHOR]

Aging is associated with loss of tissue mass and a decline in adult stem cell function in many tissues. In contrast, aging in the prostate is associated with growth-related diseases including benign prostatic hyperplasia (BPH). Surprisingly, the effects of aging on prostate epithelial cells have not been established. Here we find that organoid-forming progenitor activity of mouse prostate basal and luminal cells is maintained with age. This is caused by an age-related expansion of progenitor-like luminal cells that share features with human prostate luminal progenitor cells. The increase in luminal progenitor cells may contribute to greater risk for growth-related disease in the aging prostate. Importantly, we demonstrate expansion of human luminal progenitor cells in BPH. In summary, we define a Trop2+ luminal progenitor subset and identify an age-related shift in the luminal compartment of the mouse and human prostate epithelium. • Organoid-forming capacity is maintained in old mouse prostate epithelial cells • Identification of Trop2+ luminal cells as a progenitor-enriched subset • Trop2+ luminal progenitor cells are expanded in the aging mouse prostate • Increase in PSCA+ luminal progenitor cells in aging human prostate and BPH Aging is a significant risk factor for BPH and prostate cancer, but how aging increases disease risk in the prostate remains poorly defined. Crowell et al. show that progenitor-enriched luminal cells are expanded with aging in the mouse and human prostate, and may contribute to BPH. [ABSTRACT FROM AUTHOR]

Summary Esthesioneuroblastoma (ENB) is a rare cancer of the olfactory mucosa, with no established molecular stratification to date. We report similarities of ENB with tumors arising in the neural crest and perform integrative analysis of these tumors. We propose a molecular-based subtype classification of ENB as basal or neural, both of which have distinct pathological, transcriptomic, proteomic, and immune features. Among the basal subtype, we uncovered an IDH2 R172 mutant-enriched subgroup (∼35%) harboring a CpG island methylator phenotype reminiscent of IDH2 mutant gliomas. Compared with the basal ENB methylome, the neural ENB methylome shows genome-wide reprogramming with loss of DNA methylation at the enhancers of axonal guidance genes. Our study reveals insights into the molecular pathogenesis of ENB and provides classification information of potential therapeutic relevance. Graphical Abstract Highlights • Integrative analysis of ENBs identifies neural-like and basal-like subgroups • Approximately 35% of basal-like ENBs display IDH2 R172 hotspot mutations • ENBs with IDH2 mutations display a CpG island methylator phenotype (E-CIMP) • Basal-like ENBs display higher intratumoral-infiltrating lymphocytes Classe et al. report an integrative multi-omics analysis of esthesioneuroblastomas (ENBs) and identify two subgroups of ENBs: neural-like and basal-like. These subgroups are linked to cell ontogeny and are associated with distinct clinicopathological features and patient outcomes. Notably, one-third of basal ENBs harbor an IDH2 R172 mutation with a CpG island methylator phenotype. [ABSTRACT FROM AUTHOR]