Stromal changes in the aged lung induce an emergence from melanoma dormancy.

Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells-in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1-3. It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing4-8. We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung.

Paradoxical Role for Wild-Type p53 in Driving Therapy Resistance in Melanoma.

Metastatic melanoma is an aggressive disease, despite recent improvements in therapy. Eradicating all melanoma cells even in drug-sensitive tumors is unsuccessful in patients because a subset of cells can transition to a slow-cycling state, rendering them resistant to most targeted therapy. It is still unclear what pathways define these subpopulations and promote this resistant phenotype. In the current study, we show that Wnt5A, a non-canonical Wnt ligand that drives a metastatic, therapy-resistant phenotype, stabilizes the half-life of p53 and uses p53 to initiate a slow-cycling state following stress (DNA damage, targeted therapy, and aging). Inhibiting p53 blocks the slow-cycling phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. In vivo, this can be accomplished with a single dose of p53 inhibitor at the commencement of BRAF/MEK inhibitor therapy. These data suggest that taking the paradoxical approach of inhibiting rather than activating wild-type p53 may sensitize previously resistant metastatic melanoma cells to therapy.

The Adapted Resistance Training with Instability Randomized Controlled Trial for Gait Automaticity.

BACKGROUND: Deficits in the cerebellar locomotor region (CLR) have been associated with loss of gait automaticity in individuals with freezing of gait in Parkinson's disease (freezers); however, exercise interventions that restore gait automaticity in freezers are lacking. We evaluated the effects of the adapted resistance training with instability ([ARTI] complex exercises) compared with traditional motor rehabilitation (without complex exercises) on gait automaticity and attentional set-shifting. We also verified associations between gait automaticity change and CLR activation change previously published. METHODS: Freezers were randomized either to the experimental group (ARTI, n = 17) or to the active control group (traditional motor rehabilitation, n = 15). Both training groups performed exercises 3 times a week for 12 weeks. Gait automaticity (dual-task and dual-task cost [DTC] on gait speed and stride length), single-task gait speed and stride length, attentional set-shifting (time between Trail Making Test parts B and A), and CLR activation during a functional magnetic resonance imaging protocol of simulated step initiation task were evaluated before and after interventions. RESULTS: Both training groups improved gait parameters in single task (P < 0.05), but ARTI was more effective than traditional motor rehabilitation in improving DTC on gait speed, DTC on stride length, dual-task stride length, and CLR activation (P < 0.05). Changes in CLR activation were associated with changes in DTC on stride length (r = 0.68, P = 0.002) following ARTI. Only ARTI improved attentional set-shifting at posttraining (P < 0.05). CONCLUSIONS: ARTI restores gait automaticity and improves attentional set-shifting in freezers attributed to the usage of exercises with high motor complexity. © 2020 International Parkinson and Movement Disorder Society.

Multidisciplinary care in Amyotrophic Lateral Sclerosis: a systematic review and meta-analysis.

Multidisciplinary care (MDC) has been the most recommended approach for symptom management in amyotrophic lateral sclerosis (ALS) but there is conflicting evidence about its effectiveness on survival and quality of life (QoL) of ALS patients. We conducted a systematic review to determine the effects of multidisciplinary care compared to general neurological care in survival and quality of life of ALS patients. A comprehensive literature search using Scopus, MEDLINE-PubMed, Cochrane, Web of Science, PEDro, and Science Direct was undertaken. Studies related to multidisciplinary care or general neurological care in ALS patients that assessed survival and quality of life and were published in the period up to and including January 2020 were included. A total of 1192 studies were initially identified, but only 6 were included. All studies that investigated survival showed and advantage of MDC over NC, and this benefit was even greater for bulbar onset patients. A meta-analysis was performed and showed a mean difference of 141.67 (CI 95%, 61.48 to 221.86), indicating that patients who received MDC had longer survival than those who underwent NC (p = 0.0005). Concerning QoL, only one study found better mental health scores related to QoL for patients under MDC. Multidisciplinary care is more effective than general neurology care at improving survival of patients with ALS, but only improves mental health outcomes related to quality of life of these patients.

Phenotypic heterogeneity of hereditary diffuse gastric cancer: report of a family with early-onset disease.

BACKGROUND AND AIMS: The time course for the development of clinically significant hereditary diffuse gastric cancer (HDGC) is unpredictable. Little is known about the progression from preclinical, indolent lesions to widely invasive, aggressive phenotypes. Gastroendoscopy often fails to detect early lesions, and risk-reducing/prophylactic total gastrectomy (PTG) is the only curative approach. We present an HDGC family with early-onset disease in which clinical and histologic findings provided insight into the understanding of different HDGC phenotypes. METHODS: The proband was diagnosed at age 18 years with widely invasive, metastatic DGC. CDH1 genetic testing identified a pathogenic, germline CDH1 variant (c.1901C>T, p.Ala634Val). Thirty family members were tested, and 15 CDH1 carriers were identified. RESULTS: Six family members had PTG, with negative preoperative workup. The proband's 14-year-old sister is the youngest patient, reported to date, to have PTG after negative preoperative biopsy sampling. Intramucosal HDGC foci were detected in all PTG specimens (1-33). In contrast to the "indolent" phenotype of these foci, the aggressive DGC from the proband showed pleomorphic cells, absent E-cadherin expression, increased proliferation (Ki-67 index), and activation of oncogenic events (p53, pSrc and pStat3 overexpression). All family members had Helicobacter pylori gastritis. Cag-A-positive strains were detected in all specimens, except in the proband's sister. CONCLUSIONS: HDGC is a heterogeneous disease regarding clinical behavior, endoscopic findings, histopathologic features, and immunophenotypic/molecular profile. The presence of bizarre, pleomorphic cells in endoscopic biopsy specimens is suggestive of advanced disease and should prompt clinical intervention. The involvement of a full multidisciplinary team is essential for the management of these patients.

The pubovesical complex-sparing technique on laparoscopic radical prostatectomy.

INTRODUCTION: Preservation of urinary continence is a great challenge in Radical Prostatectomy. In order to improve functional results, Asimakopoulos et al. (2010) described a robot-assisted surgical technique with preservation of the pubovesical complex (PVC). We present a pure laparoscopic execution. PRESENTATION: A 61-year-old male patient with a diagnosis of prostate cancer, with PSA 6.54ng/ml, DRE: T1C and Gleason 6 (3+3) 1/12 fragments. All therapeutic possibilities were discussed, including active surveillance. The patient opted for surgical treatment. A transperitoneal technique was used. We started the dissection on the left side, in the limit between the detrusor and the base of the prostate. The left seminal vesicle was dissected and left neurovascular bundle released by a high anterior dissection. We repeated the same procedure on the right side. The urethra was then divided, prostatic apex was laterally drawn and PVC was released. The bladder neck was divided and an urethrovesical anastomosis was achieved. A pelvic drain was placed. RESULTS: The total operative time was 150 minutes. The estimated blood loss was 300mL. The drain was removed on the 1st postoperative day and the patient was discharged. The Foley catheter was removed after 7 days and the patient remained completely dry. Hystopathology revealed adenocarcinoma Gleason 6, negative margins. PSA after 30 days was <0.04ng/mL, and the patient reported partial penile erection. CONCLUSION: The Pubovesical Complex-Sparing Technique on Laparoscopic Radical Prostatectomy was feasible and safe. Further adequately designed studies are needed to confirm whether this technique enhances early functional outcomes.

The cytolinker plectin regulates nuclear mechanotransduction in keratinocytes.

The transmission of mechanical forces to the nucleus is important for intracellular positioning, mitosis and cell motility, yet the contribution of specific components of the cytoskeleton to nuclear mechanotransduction remains unclear. In this study, we examine how crosstalk between the cytolinker plectin and F-actin controls keratin network organisation and the 3D nuclear morphology of keratinocytes. Using micro-patterned surfaces to precisely manipulate cell shape, we find that cell adhesion and spreading regulate the size and shape of the nucleus. Disruption of the keratin cytoskeleton through loss of plectin facilitated greater nuclear deformation, which depended on acto-myosin contractility. Nuclear morphology did not depend on direct linkage of the keratin cytoskeleton with the nuclear membrane, rather loss of plectin reduced keratin filament density around the nucleus. We further demonstrate that keratinocytes have abnormal nuclear morphologies in the epidermis of plectin-deficient, epidermolysis bullosa simplex patients. Taken together, our data demonstrate that plectin is an essential regulator of nuclear morphology in vitro and in vivo and protects the nucleus from mechanical deformation.

The Comfort app prototype: introducing a web-based application for monitoring comfort in palliative care.

AIM: To introduce a web-based application for monitoring comfort in patients receiving palliative care. METHODS: Multi-phase electronic application development process that concluded with a pilot design to assess the feasibility and acceptability of the developed app (n=7 patients). RESULTS: The app is compatible with Android, iOS and Windows. The results from phases I and II provided the knowledge about monitoring comfort. In phase III, five experts analysed the content of the app. The assessment of comfort comprises 11 self-reported items (pain, tiredness, drowsiness, nausea, lack of appetite, shortness of breath, depression, anxiety, fear of the future, peace and the will to live). In phase IV, a total of 117 messages were retrieved. Participants considered the app simple, easy to use and useful. CONCLUSIONS: This prototype is feasible and user-friendly. Further research is needed to continue the app development, particularly in terms of data protection.

High pressure-promoted xylanase treatment to enhance papermaking properties of recycled pulp.

Industrially produced bleached recycled pulp (R) comprising essentially hardwood fibres was subjected to enzymatic treatment with endo-xylanase from Thermomyces lanuginosus with or without ultra-high hydrostatic pressure (UHP) pre-treatment at 300-600 MPa for 10 min. The kinetics and the extent of enzymatic hydrolysis after UHP pre-treatment under different conditions have been evaluated by released reducing sugars and the analysis of neutral sugars in pulps, respectively. The changes in surface chemical composition of pulps were assessed by UV-vis diffuse reflectance spectroscopy. UHP-pre-treated R under optimal conditions (400 MPa), with or without posterior enzymatic treatment, was used for the production of handsheets and evaluation of its mechanical properties. It was suggested that enzymatic modification improves significantly the papermaking properties of recycled pulp. These improvements were related with selective removal of xylan bound to impurities and to aggregated cellulose fibrils on the fibre surface, thus favouring the ensuing swelling and inter-fibre bonding in paper. UHP pre-treatment and posterior enzymatic treatment revealed a synergetic effect on the mechanical properties of recycled pulp. This fact was assigned to enhanced accessibility of fibres towards xylanase and by forced hydration and favourable rearrangement of cellulosic fibrils in fibres after UHP pre-treatment. The increase of basic strength properties after UHP-promoted xylanase treatment was up to 30 % being the most pronounced for the tensile strength and the burst resistance.

Identification of type III secretion substrates of Chlamydia trachomatis using Yersinia enterocolitica as a heterologous system.

BACKGROUND: Chlamydia trachomatis is an obligate intracellular human pathogen causing ocular and urogenital infections that are a significant clinical and public health concern. This bacterium uses a type III secretion (T3S) system to manipulate host cells, through the delivery of effector proteins into their cytosol, membranes, and nucleus. In this work, we aimed to find previously unidentified C. trachomatis T3S substrates. RESULTS: We first analyzed the genome of C. trachomatis L2/434 strain for genes encoding mostly uncharacterized proteins that did not appear to possess a signal of the general secretory pathway and which had not been previously experimentally shown to be T3S substrates. We selected several genes with these characteristics and analyzed T3S of the encoding proteins using Yersinia enterocolitica as a heterologous system. We identified 23 C. trachomatis proteins whose first 20 amino acids were sufficient to drive T3S of the mature form of ß-lactamase TEM-1 by Y. enterocolitica. We found that 10 of these 23 proteins were also type III secreted in their full-length versions by Y. enterocolitica, providing additional support that they are T3S substrates. Seven of these 10 likely T3S substrates of C. trachomatis were delivered by Y. enterocolitica into host cells, further suggesting that they could be effectors. Finally, real-time quantitative PCR analysis of expression of genes encoding the 10 likely T3S substrates of C. trachomatis showed that 9 of them were clearly expressed during infection of host cells. CONCLUSIONS: Using Y. enterocolitica as a heterologous system, we identified 10 likely T3S substrates of C. trachomatis (CT053, CT105, CT142, CT143, CT144, CT161, CT338, CT429, CT656, and CT849) and could detect translocation into host cells of CT053, CT105, CT142, CT143, CT161, CT338, and CT429. Therefore, we revealed several C. trachomatis proteins that could be effectors subverting host cell processes.

Complex Exercises Improve Cognition in People With Parkinson's Disease and Freezing of Gait.

BACKGROUND: Evidence has suggested that cognitive decline may be a risk factor for freezing of gait (FOG) in Parkinson's disease (PD). Complex and challenging exercises have been suggested as potential rehabilitation strategies to decrease FOG severity and improve cognition; however, it is unknown whether improvement in cognition would explain decreased FOG severity following exercise. OBJECTIVE: In this secondary analysis, we evaluated the effects of the adapted resistance training with instability (ARTI-complex and challenging exercises) compared with traditional motor rehabilitation (TMR-without challenging exercises) on cognitive function in people with FOG of PD. We also verified whether cognitive improvement explains the decrease in FOG previously published. METHODS: Participants were randomized to either the experimental group (ARTI, n = 17) or the active control group (TMR, n = 15). Both training groups exercised 3 times a week for 12 weeks (80-90 minute each session). FOG severity (FOG ratio from inertial sensors during a 360° turning-in-place task), frontal lobe function (Frontal Assessment Battery [FAB]), global cognition (Montreal Cognitive Assessment [MoCA]), and attention and psychomotor speed (Digit Symbol Substitution Test [DSST]) were evaluated before and after interventions. RESULTS: Only the ARTI group improved FAB, MoCA, and DSST scores at posttraining. In addition, ARTI was more effective than TMR in improving FAB scores at posttraining. The changes in FAB scores explained the changes in FOG ratio following ARTI (R2 = .43, P < .01). CONCLUSIONS: This pilot study suggests that ARTI, a complex and challenging training, improves cognition in people with FOG of PD. Improvements in frontal lobe function with ARTI help explain decreased FOG severity.

Telerehabilitation by Videoconferencing for Balance and Gait in People with Parkinson's Disease: A Scoping Review.

Although supervised and real-time telerehabilitation by videoconferencing is now becoming common for people with Parkinson's disease (PD), its efficacy for balance and gait is still unclear. This paper uses a scoping approach to review the current evidence on the effects of telerehabilitation by videoconferencing on balance and gait for patients with PD. We also explored whether studies have used wearable technology during telerehabilitation to assess and treat balance and gait via videoconferencing. Literature searches were conducted using PubMed, ISI's Web of Knowledge, Cochrane's Library, and Embase. The data were extracted for study design, treatment, and outcomes. Fourteen studies were included in this review. Of these, seven studies investigated the effects of telerehabilitation (e.g., tele-yoga and adapted physiotherapy exercises) on balance and gait measures (e.g., self-reported balance, balance scale, walking speed, mobility, and motor symptoms) using videoconferencing in both assessment and treatment. The telerehabilitation programs by videoconferencing were feasible and safe for people with PD; however, the efficacy still needs to be determined, as only four studies had a parallel group. In addition, no study used wearable technology. Robust evidence of the effects of telerehabilitation by videoconferencing on balance and gait for patients with PD was not found, suggesting that future powered, prospective, and robust clinical trials are needed.

5-HT1A and 5-HT2A receptor effects on recognition memory, motor/exploratory behaviors, emotionality and regional dopamine transporter binding in the rat.

Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HT1AR agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HT2AR agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3 mg/kg), WAY100,635 (0.4 mg/kg), DOI (0.1 mg/kg), ALT (1 mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HT1AR inhibition and 5-HT2AR activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.

2,5-Dimethoxy-4-iodoamphetamine and altanserin induce region-specific shifts in dopamine and serotonin metabolization pathways in the rat brain.

PURPOSE: For understanding the neurochemical mechanism of neuropsychiatric conditions associated with cognitive deficits it is of major relevance to elucidate the influence of serotonin (5-HT) agonists and antagonists on memory function as well dopamine (DA) and 5-HT release and metabolism. In the present study, we assessed the effects of the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and the 5-HT2A receptor altanserin (ALT) on object and place recognition memory and cerebral neurotransmitters and metabolites in the rat. METHODS: Rats underwent a 5-min exploration trial in an open field with two identical objects. After systemic injection of a single dose of either DOI (0.1 mg/kg), ALT (1 mg/kg) or the respectice vehicle (0.9 % NaCl, 50 % DMSO), rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Upon the assessment of object exploration and motor/exploratory behaviors, rats were sacrificed. DA, 5-HT and metabolite levels were analyzed in cingulate (CING), caudateputamen (CP), nucleus accumbens (NAC), thalamus (THAL), dorsal (dHIPP) and ventral hippocampus (vHIPP), brainstem and cerebellum with high performance liquid chromatography. RESULTS: DOI decreased rearing but increased head-shoulder motility relative to vehicle. Memory for object and place after both DOI and ALT was not different from vehicle. Network analyses indicated that DOI inhibited DA metabolization in CING, CP, NAC, and THAL, but facilitated it in dHIPP. Likewise, DOI inhibited 5-HT metabolization in CING, NAC, and THAL. ALT facilitated DA metabolization in the CING, NAC, dHIPP, vHIPP, and CER, but inhibited it in the THAL. Additionally, ALT facilitated 5-HT metabolization in NAC and dHIPP. CONCLUSIONS: DOI and ALT differentially altered the quantitative relations between the neurotransmitter/metabolite levels in the individual brain regions, by inducing region-specific shifts in the metabolization pathways. Findings are relevant for understanding the neurochemistry underlying DAergic and/or 5-HTergic dysfunction in neurological and psychiatric conditions.

Tensile and Tearing Properties of a Geocomposite Mechanically Damaged by Repeated Loading and Abrasion.

The behaviour of geosynthetics can be affected by many agents, both in the short and long term. Mechanical damage caused by repeated loading or abrasion are examples of agents that may induce undesirable changes in the properties of geosynthetics. The research conducted in this work complemented previous studies and consisted of submitting a geocomposite, isolated and successively, to two degradation tests: mechanical damage under repeated loading and abrasion. The geocomposite (a nonwoven geotextile reinforced with polyethylene terephthalate filaments) was tested on both sides (with or without filaments) and directions (machine and cross-machine). The impact of the degradation tests on the geocomposite was quantified by monitoring changes in its tensile and tearing behaviour. The results showed that, in most cases, the degradation tests caused the deterioration of the tensile and tearing behaviour of the geocomposite, affecting its reinforcement function. The decline in tensile strength correlated reasonably well with the decline in tearing strength. Changing the side and direction tested influenced, in some cases (those involving abrasion), the degradation experienced by the geocomposite. The reduction factors (referring to tensile and tearing strength) for the combined effect of the degradation agents tended to be lower when determined by using the common method (compared to those resulting directly from the successive exposure to both agents).

Adult Colocolic Intussusception: A Rare Case of Intestinal Obstruction.

Intussusception occurs when a part of the intestine slides into its distal adjacent portion and is a surgical emergency. Adult colocolic intussusception is rare, but it is a severe condition and is usually associated with a presence of a tumoral process. We present the case of a frail male patient admitted to our emergency department with abdominal pain, prostration, and dyspnea. The patient was diagnosed with colocolic intussusception and was submitted to a subtotal colectomy and ileostomy. Patients with colocolic intussusception usually present with chronic abdominal pain and signs of intestinal obstruction. Abdominal CT scan facilitates the diagnosis, but most cases are only diagnosed intraoperatively. Given the high probability of colon cancer, the treatment involves an oncological resection of the intestinal segment. Colocolic intussusception is a rare cause of intestinal obstruction in adults where a high suspicion index is of paramount importance, especially considering that most of the diagnoses are made at surgery.