Diego Herazo, delantero colombiano que debutó con San Lorenzo de Argentina este martes, habló con El Alargue de Caracol Radio sobre lo que fue su estreno con el equipo de Almagro. Herazo se refirió, entre otras cosas, al apodo que ha recibido de parte de la prensa de ese país, quien lo ha bautizado como el ‘Lukaku colombiano’.

Logic’s new album, College Park, is his first record as an independent artist after parting ways with Def Jam. He tells Tom Power about the ups and downs of major labels, his turbulent early life and how he has prevailed in spite of setbacks.

WHEN you meet Peter Chalouhy it is hard to imagine the bubbly little boy may not make it to his 14th birthday. A stem cell gene therapy trial is his only hope but funds are needed to bring it here.

Anyone seeking to become part of Colorado’s psychedelics industry by growing mushrooms, operating a healing center, or manufacturing psilocybin edibles now has guidance on how to do so legally.

When psychedelic-assisted therapy becomes available in Colorado next year, the state will be just the second in the U.S. to regulate the production and use of psilocybin mushrooms.

On October 27, Bermuda will join the global community in celebrating World Occupational Therapy Day, recognizing the vital contributions of Occupational Therapists [OTs] who empower individuals to engage fully in daily life and promoting the 2024 theme, “Occupational Therapy for All.” A Government spokesperson said, “World Occupational Therapy Day will be celebrated on October 27th, […]

1. Second Nine news executive leaves in wake of cultural review  Sydney Morning Herald
2. Nine executive quits embattled network  news.com.au
3. Another executive departs beleaguered Nine Network  Daily Telegraph

1. Corporate regulator sues Cbus over unresolved insurance claims  Sydney Morning Herald
2. VIDEO Cbus taken to court accused of failing to pay thousands of claims  ABC News
3. Super fund in strife over $20m in delayed payments  The Canberra Times

1. Volcanic eruption grounds Bali flights, leaving travellers stranded  Sydney Morning Herald
2. Bali flight cancellations continue due to dangerous volcanic ash clouds  SBS News
3. Bali flight cancellations continue as volcano spews ash  9News
4. Aussies stranded in Bali volcano nightmare  Daily Telegraph

1. As it happened: Donald Trump ally taunts Kevin Rudd; WiseTech shareholders launch class action  Sydney Morning Herald
2. Ditching Rudd over Trump insults would be ‘worst possible signal’: Turnbull  Sydney Morning Herald
3. Senior Liberal calls for Rudd to be sacked after Trump advisor suggests US ambassador is on thin ice  9News

1. Kristian White trial: CCTV reveals final moments before Clare Nowland Tasering in Cooma nursing home  Sydney Morning Herald
2. Jury shown footage of 95yo getting stuck in tree in weeks before being tasered by police officer  ABC News
3. Elderly woman 'unable to comply' before cop Tasered her, court hears  9News

The European Space Agency (ESA) is preparing to launch a mission to study the aftermath of DART's impact on the asteroid moonlet Dimorphos.

The European Space Agency’s Hera spacecraft launched on Oct. 7, 2024, from Cape Canaveral, Florida. It will travel to the Didymos-Dimorphos asteroid system to study the aftermath of the first-ever field test of an asteroid deflection technique.

Systematic review produced by the EPPI-Centre in 2015.This systematic review aimed to evaluate the effect of HAART and ARV monotherapy on liver disease progression and liver-related mortality in individuals co-infected with HIV and hepatitis C, including in patients with haemophilia.

Give yourself an extra relaxation boost with an aromatherapy pillow that you’ll customize with fabric and essential oils of your own choosing. The pillow can be hand-stitched or you can use a Makerspace-provided sewing machine. All supplies will be provided. Drop-ins welcome! Come for the entire time or only part of the session. Registration is optional, but if you know you’ll be attending please register so we can anticipate the number of people to expect.

Hyperbaric Oxygen Therapy (HBOT) is a medical treatment that involves breathing pure oxygen in a pressurized environment. This unique treatment method has shown effectiveness in healing various conditions, from complex wound healing to treating decompression sickness in divers. HBOT works on the principle of increasing oxygen concentration in the body, which can enhance the body’s ... Read more

The post How Much Does Hyperbaric Oxygen Therapy Cost? Price Tips appeared first on Star Two.

Jet lag is a common issue for anyone crossing multiple time zones. While various remedies exist, massage therapy stands out as an effective, natural method to help the body adjust and recover. This guide explores how this therapy can be utilized to alleviate the symptoms of jet lag, offering practical tips and techniques that can ... Read more

The post Massage Therapy for Frequent Travelers – Tips for Reducing Jet Lag appeared first on Star Two.

The genetic testing company 23andMe announced it will cut 40% of its workforce, or 200 jobs, and halt the work on therapies it was developing. As the BBC notes, the company is fighting for survival after hackers gained access to personal information of millions of its users, causing the stock to crater by more than 70%. All seven of its independent directors also resigned in September, following a protracted negotiation with founder and Chief Executive Anne Wojcicki over her plan to take the company private. The BBC reports: On Tuesday, the company warned investors of "substantial doubt" about its ability to continue operating, as it reported that revenue had fallen to $44 million between July and September compared to $50 million in the same period last year. Losses fell to $59 million from $75 million. The job cuts are expected to lead to one-off costs of $12 million, including severance pay, for the plan that will result in savings of $35 million. "We are taking these difficult but necessary actions as we restructure 23andMe and focus on the long-term success of our core consumer business and research partnerships," Ms Wojcicki said. The company also said it is considering what to do with the therapies it had in development, including licensing or selling them. 23andMe is a giant of the growing ancestor-tracing industry. It offers genetic testing from DNA, with ancestry breakdown and personalised health insights. Its customers include famous names, from rapper Snoop Dogg to multi-billionaire investor Warren Buffett. The company was valued at roughly $3.5 billion when it listed on the Nasdaq stock exchange in 2021 and its share price peaked at $17.65. But they have since tumbled and are currently trading at less than $5.

Read more of this story at Slashdot.

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Alison M. Kurimchak
Dec 1, 2020; 19:2068-2089
Research

Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.

The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.

Nicholas D. LeBlond
Dec 1, 2020; 61:1697-1706
Research Articles

The dysregulation of myeloid-derived cell metabolism can drive atherosclerosis. AMP-activated protein kinase (AMPK) controls various aspects of macrophage dynamics and lipid homeostasis, which are important during atherogenesis. Using LysM-Cre to drive the deletion of both the α1 and α2 catalytic subunits (MacKO), we aimed to clarify the role of myeloid-specific AMPK signaling in male and female mice made acutely atherosclerotic by injection of AAV vector encoding a gain-of-function mutant PCSK9 (PCSK9-AAV) and WD feeding. After 6 weeks of WD feeding, mice received a daily injection of either the AMPK activator A-769662 or a vehicle control for an additional 6 weeks. Following this (12 weeks total), we assessed myeloid cell populations and differences between genotype or sex were not observed. Similarly, aortic sinus plaque size, lipid staining, and necrotic area did not differ in male and female MacKO mice compared with their littermate floxed controls. Moreover, therapeutic intervention with A-769662 showed no treatment effect. There were also no observable differences in the amount of circulating total cholesterol or triglyceride, and only minor differences in the levels of inflammatory cytokines between groups. Finally, CD68+ area and markers of autophagy showed no effect of either lacking AMPK signaling or AMPK activation. Our data suggest that while defined roles for each catalytic AMPK subunit have been identified, complete deletion of myeloid AMPK signaling does not significantly impact atherosclerosis. Additionally, these findings suggest that intervention with the first-generation AMPK activator A-769662 is not able to stem the progression of atherosclerosis.

Renal Cell Carcinoma (RCC) is one of the most commonly diagnosed cancers worldwide with research efforts dramatically improving understanding of the biology of the disease. To investigate the role of the immune system in treatment-naïve clear cell Renal Cell Carcinoma (ccRCC), we interrogated the immune infiltrate in patient-matched ccRCC tumor samples, benign normal adjacent tissue (NAT) and peripheral blood mononuclear cells (PBMCs isolated from whole blood, focusing our attention on the myeloid cell infiltrate. Using flow cytometric, MS, and ExCYT analysis, we discovered unique myeloid populations in PBMCs across patient samples. Furthermore, normal adjacent tissues and ccRCC tissues contained numerous myeloid populations with a unique signature for both tissues. Enrichment of the immune cell (CD45⁺) fraction and subsequent gene expression analysis revealed a number of myeloid-related genes that were differentially expressed. These data provide evidence, for the first time, of an immunosuppressive and pro-tumorigenic role of myeloid cells in early, clinically localized ccRCC. The identification of a number of immune proteins for therapeutic targeting provides a rationale for investigation into the potential efficacy of earlier intervention with single-agent or combination immunotherapy for ccRCC.

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States, with limited effective targeted therapies. Endometrial tumors exhibit frequent alterations in protein kinases, yet only a small fraction of the kinome has been therapeutically explored. To identify kinase therapeutic avenues for EC, we profiled the kinome of endometrial tumors and normal endometrial tissues using Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). Our proteomics analysis identified a network of kinases overexpressed in tumors, including Serine/Arginine-Rich Splicing Factor Kinase 1 (SRPK1). Immunohistochemical (IHC) analysis of endometrial tumors confirmed MIB-MS findings and showed SRPK1 protein levels were highly expressed in endometrioid and uterine serous cancer (USC) histological subtypes. Moreover, querying large-scale genomics studies of EC tumors revealed high expression of SRPK1 correlated with poor survival. Loss-of-function studies targeting SRPK1 in an established USC cell line demonstrated SRPK1 was integral for RNA splicing, as well as cell cycle progression and survival under nutrient deficient conditions. Profiling of USC cells identified a compensatory response to SRPK1 inhibition that involved EGFR and the up-regulation of IGF1R and downstream AKT signaling. Co-targeting SRPK1 and EGFR or IGF1R synergistically enhanced growth inhibition in serous and endometrioid cell lines, representing a promising combination therapy for EC.

This article has been withdrawn by the authors. This article did not comply with the editorial guidelines of MCP. Specifically, single peptide based protein identifications of 9-19% were included in the analysis and discussed in the results and conclusions. We wish to withdraw this article and resubmit a clarified, corrected manuscript for review.

Radiolabeled small-molecule DOTA-haptens can be combined with antitumor/anti-DOTA bispecific antibodies (BsAbs) for pretargeted radioimmunotherapy (PRIT). For optimized delivery of the theranostic - and β-emitting isotope ¹⁷⁷Lu with DOTA-based PRIT (DOTA-PRIT), bivalent Gemini (DOTA-Bn-thiourea-PEG4-thiourea-Bn-DOTA, aka (3,6,9,12-tetraoxatetradecane-1,14-diyl)bis(DOTA-benzyl thiourea)) was developed. Methods: Gemini was synthesized by linking 2 S-2-(4-isothiocyanatobenzyl)-DOTA molecules together via a 1,14-diamino-PEG4 linker. [¹⁷⁷Lu]Lu-Gemini was prepared with no-carrier-added ¹⁷⁷LuCl₃ to a molar-specific activity of 123 GBq/μmol and radiochemical purity of more than 99%. The specificity of BsAb-¹⁷⁷Lu-Gemini was verified in vitro. Subsequently, we evaluated biodistribution and whole-body clearance for [¹⁷⁷Lu]Lu-Gemini and, for comparison, our gold-standard monovalent [¹⁷⁷Lu]Lu-S-2-(4-aminobenzyl)-DOTA ([¹⁷⁷Lu]Lu-DOTA-Bn) in naïve (tumor-free) athymic nude mice. For our proof-of-concept system, a 3-step pretargeting approach was performed with an established DOTA-PRIT regimen (anti-GPA33/anti-DOTA IgG-scFv BsAb, a clearing agent, and [¹⁷⁷Lu]Lu-Gemini) in mouse models. Results: Initial in vivo studies showed that [¹⁷⁷Lu]Lu-Gemini behaved similarly to [¹⁷⁷Lu]Lu-DOTA-Bn, with almost identical blood and whole-body clearance kinetics, as well as biodistribution and mouse kidney dosimetry. Pretargeting [¹⁷⁷Lu]Lu-Gemini to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [¹⁷⁷Lu]Lu-Gemini for blood, tumor, liver, spleen, and kidneys of 3.99, 455, 6.93, 5.36, and 14.0 cGy/MBq, respectively. Tumor–to–normal tissue absorbed-dose ratios (i.e., therapeutic indices [TIs]) for the blood and kidneys were 114 and 33, respectively. In addition, we demonstrate that the use of bivalent [¹⁷⁷Lu]Lu-Gemini in DOTA-PRIT leads to improved TIs and augmented [¹⁷⁷Lu]Lu-Gemini tumor uptake and retention in comparison to monovalent [¹⁷⁷Lu]Lu-DOTA-Bn. Finally, we established efficacy in SW1222 tumor-bearing mice, demonstrating that a single injection of anti-GPA33 DOTA-PRIT with 44 MBq (1.2 mCi) of [¹⁷⁷Lu]Lu-Gemini (estimated tumor-absorbed dose, 200 Gy) induced complete responses in 5 of 5 animals and a histologic cure in 2 of 5 (40%) animals. Moreover, a significant increase in survival compared with nontreated controls was noted (maximum tolerated dose not reached). Conclusion: We have developed a bivalent DOTA-radiohapten, [¹⁷⁷Lu]Lu-Gemini, that showed improved radiopharmacology for DOTA-PRIT application. The use of bivalent [¹⁷⁷Lu]Lu-Gemini in DOTA-PRIT, as opposed to monovalent [¹⁷⁷Lu]Lu-DOTA-Bn, allows curative treatments with considerably less administered ¹⁷⁷Lu activity while still achieving high TIs for both the blood (>100) and the kidneys (>30).

Fibroblast activation protein (FAP) is abundantly expressed in the stroma of most human solid tumors. Clinical-stage radiolabeled FAP ligands are increasingly used as tools for the detection of various cancer lesions. To unleash the full therapeutic potential of FAP-targeting agents, ligands need to remain at the tumor site for several days after administration. We recently described the discovery of OncoFAP, a high-affinity small organic ligand of FAP with a rapid accumulation in tumors and low uptake in healthy tissues in cancer patients. Trimerization of OncoFAP provided a derivative (named TriOncoFAP, or OncoFAP-23) with improved FAP affinity. In this work, we evaluated the tissue biodistribution profile and the therapeutic performance of OncoFAP-23 in tumor-bearing mice. Methods: OncoFAP-23 was radiolabeled with the theranostic radionuclide ¹⁷⁷Lu. Preclinical experiments were conducted on mice bearing SK-RC-52.hFAP (BALB/c nude mice) or CT-26.hFAP (BALB/c mice) tumors. ¹⁷⁷Lu-OncoFAP and ¹⁷⁷Lu-FAP-2286 were included in the biodistribution study as controls. Toxicologic evaluation was performed on Wistar rats and CD1 mice by injecting high doses of OncoFAP-23 or its cold-labeled counterpart, respectively. Results: ¹⁷⁷Lu-OncoFAP-23 emerged for its best-in-class biodistribution profile, high and prolonged tumor uptake (i.e., ~16 percentage injected dose/g at 96 h), and low accumulation in healthy organs, which correlates well with its potent single-agent anticancer activity at low levels of administered radioactivity. Combination treatment with the tumor-targeted interleukin 2 (L19-IL2, a clinical-stage immunocytokine) further expands the therapeutic window of ¹⁷⁷Lu-OncoFAP-23 by potentiating its in vivo antitumor activity. Proteomics studies revealed a potent tumor-directed immune response on treatment with the combination. OncoFAP-23 and ^natLu-OncoFAP-23 exhibited a favorable toxicologic profile, without showing any side effects or signs of toxicity. Conclusion: OncoFAP-23 presents enhanced tumor uptake and tumor retention and low accumulation in healthy organs, findings that correspond to a strongly improved in vivo antitumor efficacy. The data presented in this work support the clinical development of ¹⁷⁷Lu-OncoFAP-23 for the treatment of FAP-positive solid tumors.

Single-domain antibodies (sdAbs) demonstrate favorable pharmacokinetic profiles for molecular imaging applications. However, their renal excretion and retention are obstacles for applications in targeted radionuclide therapy (TRT). Methods: Using a click-chemistry–based pretargeting approach, we aimed to reduce kidney retention of a fibroblast activation protein α (FAP)–targeted sdAb, 4AH29, for ¹⁷⁷Lu-TRT. Key pretargeting parameters (sdAb-injected mass and lag time) were optimized in healthy mice and U87MG (FAP⁺) xenografts. A TRT study in a pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (PDX) model was performed as a pilot study for sdAb-based pretargeting applications. Results: Modification of 4AH29 with trans-cyclooctene (TCO) moieties did not modify the sdAb pharmacokinetic profile. A 200-µg injected mass of 4AH29-TCO and an 8-h lag time for the injection of [¹⁷⁷Lu]Lu-DOTA-PEG₇-tetrazine resulted in the highest kidney therapeutic index (2.0 ± 0.4), which was 5-fold higher than that of [¹⁷⁷Lu]Lu-DOTA-4AH29 (0.4 ± 0.1). FAP expression in the tumor microenvironment was validated in a PDAC PDX model with both immunohistochemistry and PET/CT imaging. Mice treated with the pretargeting high-activity approach (4AH29-TCO + [¹⁷⁷Lu]Lu-DOTA-PEG₇-tetrazine; 3 x 88 MBq, 1 injection per week for 3 wk) demonstrated prolonged survival compared with the vehicle control and conventionally treated ([¹⁷⁷Lu]Lu-DOTA-4AH29; 3 x 37 MBq, 1 injection per week for 3 wk) mice. Mesangial expansion was reported in 7 of 10 mice in the conventional cohort, suggesting treatment-related kidney morphologic changes, but was not observed in the pretargeting cohort. Conclusion: This study validates pretargeting to mitigate sdAbs’ kidney retention with no observation of morphologic changes on therapy regimen at early time points. Clinical translation of click-chemistry–based pre-TRT is warranted on the basis of its ability to alleviate toxicities related to biovectors’ intrinsic pharmacokinetic profiles. The absence of representative animal models with extensive stroma and high FAP expression on cancer-associated fibroblasts led to a low mean tumor-absorbed dose even with high injected activity and consequently to modest survival benefit in this PDAC PDX.

Genetic-testing lab 23andMe plans to cut its workforce by 40% and end its therapeutics program in an effort to cut costs, the company announced Monday.

Genetic-testing lab 23andMe plans to cut its workforce by 40% and end its therapeutics program in an effort to cut costs, the company announced Monday.

The therapy helps the brain work more efficiently and lifts depression.

Many people who want to be healthy often try to eat a balanced diet and get regular exercise. However, most foods today simply do not contain the nutrition they did in the past. If your goal is to improve your physical and mental health, your body may still require essential nutrients. IV nutrition therapy is […]

The post Exploring the Impact of IV Nutrition Therapy on Mental Health first appeared on What is Psychology?.

EMDR therapy, also known as Eye Movement Desensitization and Reprocessing therapy, is an integrative and all-inclusive psychotherapy model used to treat mental conditions and trauma. This approach has been researched extensively in recent years and confirmed to be an effective way to tackle mental challenges. EMDR therapy was reportedly developed in the 1980’s by an […]

The post What are The Different Phases of EMDR Therapy? first appeared on What is Psychology?.

Are you a clinician looking to master CBT for Perfectionism? Or, learn more about the CBT model of perfectionism below. CBT Model of Perfectionism Perfectionism is not the same thing as conscientiousness. For example, in a recent study of older adults, perfectionism was both associated with increased risk of mortality whereas conscientiousness was associated with […]

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