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Vault RNAs (vtRNAs) are evolutionarily conserved small noncoding RNAs transcribed by RNA polymerase III. Vault RNAs were initially described as components of the vault particle, but have since been assigned multiple vault-independent functions, including regulation of PKR activity, apoptosis, autophagy, lysosome biogenesis, and viral particle trafficking. The full-length transcript has also been described as a noncanonical source of miRNAs, which are processed in a DICER-dependent manner. As central molecules in vault-dependent and independent processes, vtRNAs have been attributed numerous biological roles, including regulation of cell proliferation and survival, response to viral infections, drug resistance, and animal development. Yet, their impact to mammalian physiology remains largely unexplored. To study vault RNAs in vivo, we generated a mouse line with a conditional Vaultrc5 loss-of-function allele. Because Vaultrc5 is the sole murine vtRNA, this allele enables the characterization of the physiological requirements of this conserved class of small regulatory RNAs in mammals. Using this strain, we show that mice constitutively null for Vaultrc5 are viable and histologically normal but have a slight reduction in platelet counts, pointing to a potential role for vtRNAs in hematopoiesis. This work paves the way for further in vivo characterizations of this abundant but mysterious RNA molecule. Specifically, it enables the study of the biological consequences of constitutive or lineage-specific Vaultrc5 deletion and of the physiological requirements for an intact Vaultrc5 during normal hematopoiesis or in response to cellular stresses such as oncogene expression, viral infection, or drug treatment.

Early detection of drug-drug interactions (DDIs) can facilitate timely drug development decisions, prevent unnecessary restrictions on patient enrollment, resulting in clinical study populations that are not representative of the indicated study population, and allow for appropriate dose adjustments to ensure safety in clinical trials. All of these factors contribute to a streamlined drug approval process and enhanced patient safety. Here we describe a new approach for early prediction of the magnitude of change in exposure for cytochrome P450 (P450) CYP3A4-related DDIs of small-molecule anticancer drugs based on the model-based extrapolation of human-CYP3A4-transgenic mice pharmacokinetics to humans. Victim drugs brigatinib and lorlatinib were evaluated with the new approach in combination with the perpetrator drugs itraconazole and rifampicin. Predictions of the magnitude of change in exposure deviated at most 0.99- to 1.31-fold from clinical trial results for inhibition with itraconazole, whereas exposure predictions for the induction with rifampicin were less accurate, with deviations of 0.22- to 0.48-fold. Results for the early prediction of DDIs and their clinical impact appear promising for CYP3A4 inhibition, but validation with more victim and perpetrator drugs is essential to evaluate the performance of the new method.

A STING (stimulator of interferon genes) agonist GSK3996915 under investigation in early discovery for hepatitis B was orally dosed to a mouse model for understanding the parent drug distribution in liver, the target organ. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to quantify the distribution of GSK3996915 in liver collected from mice administered a single oral dose at 90 mg/kg. GSK3996915 was detected with a zonal distribution localized in the portal triad and highly concentrated in the main bile ducts, indicating clearance through biliary excretion. High spatial resolution imaging showed the distribution of the parent drug localized to the cellular populations in the sinusoids, including the Kupffer cells. Additionally, a series of drug-related metabolites were observed to be localized in the central zones of the liver. These results exemplify the potential of utilizing MALDI IMS for measuring not only quantitative drug distribution and target exposure but also drug metabolism and elimination in a single suite of experiments.

Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management. Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between laboratories or parse out potential sex differences that could be present. We chose five minor cannabinoids found in lower quantities within Cannabis: cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), 8-tetrahydrocannabinol (8-THC), and 9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice. We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high-dose 8-THC evoked some tetrad behaviors in both sexes, while THCV and low-dose 8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential.

People with sickle cell disease (SCD) often experience chronic pain as well as unpredictable episodes of acute pain, which significantly affects their quality of life and life expectancy. Current treatment strategies for SCD-associated pain primarily rely on opioid analgesics, which have limited efficacy and cause serious adverse effects. Cannabis has emerged as a potential alternative, yet its efficacy remains uncertain. In this study, we investigated the antinociceptive effects of ⁹-tetrahydrocannabinol (THC), cannabis’ intoxicating constituent, in male HbSS mice, which express >99% human sickle hemoglobin, and male HbAA mice, which express normal human hemoglobin A, as a control. Acute THC administration (0.1–3 mg/kg^–1, i.p.) dose-dependently reduced mechanical and cold hypersensitivity in human sickle hemoglobin (HbSS) but not human normal hemoglobin A (HbAA) mice. In the tail-flick assay, THC (1 and 3 mg/kg^–1, i.p.) produced substantial antinociceptive effects in HbSS mice. By contrast, THC (1 mg/kg^–1, i.p.) did not alter anxiety-like behavior (elevated plus maze) or long-term memory (24-hour novel object recognition). Subchronic THC treatment (1 and 3 mg/kg^–1, i.p.) provided sustained relief of mechanical hypersensitivity but led to tolerance in cold hypersensitivity in HbSS mice. Together, the findings identify THC as a possible therapeutic option for the management of chronic pain in SCD. Further research is warranted to elucidate its mechanism of action and possible interaction with other cannabis constituents.

This single-center, single-arm, phase II trial (ChiCTR2100050057) investigated the ability of ¹⁸F-labeled fibroblast activation protein inhibitor ([¹⁸F]AlF-NOTA-FAPI-04, denoted as ¹⁸F-FAPI) PET/CT to predict the response to neoadjuvant camrelizumab plus chemotherapy (nCC) in locally advanced esophageal squamous cell carcinoma (LA-ESCC). Methods: This study included 32 newly diagnosed LA-ESCC participants who underwent ¹⁸F-FAPI PET/CT at baseline, of whom 23 also underwent scanning after 2 cycles of nCC. The participants underwent surgery after 2 cycles of nCC. Recorded PET parameters included maximum, peak, and mean SUVs and tumor-to-background ratios (TBRs), metabolic tumor volume, and total lesion FAP expression. PET parameters were compared between patient groups with good and poor pathologic responses, and the predictive performance for treatment response was analyzed. Results: The good and poor response groups each included 16 participants (16/32, 50.0%). On ¹⁸F-FAPI PET/CT, the posttreatment SUVs were significantly lower in good responders than in poor responders, whereas the changes in SUVs with treatment were significantly higher (all P < 0.05). SUV_max (area under the curve [AUC], 0.87; P = 0.0026), SUV_peak (AUC, 0.89; P = 0.0017), SUV_mean (AUC, 0.88; P = 0.0021), TBR_max (AUC, 0.86; P = 0.0031), and TBR_mean (AUC, 0.88; P = 0.0021) after nCC were significant predictors of pathologic response to nCC, with sensitivities of 63.64%–81.82% and specificities of 83.33%–100%. Changes in SUV_max (AUC, 0.81; P = 0.0116), SUV_peak (AUC, 0.82; P = 0.0097), SUV_mean (AUC, 0.81; P = 0.0116), and TBR_mean (AUC, 0.74; P = 0.0489) also were significant predictors of the pathologic response to nCC, with sensitivities and specificities in similar ranges. Conclusion: ¹⁸F-FAPI PET/CT parameters after treatment and their changes from baseline can predict the pathologic response to nCC in LA-ESCC participants.

Lung cancer is one of the leading causes of death worldwide. It can broadly be divided into small cell lung cancer (SCLC) and nonsmall cell lung cancer. There have been many advances over the recent years in both fields. The purpose of this review is to provide a concise summary of SCLC for the general respiratory readership.

Palliative care pertains to the holistic multidimensional concept of "patient-centred" care. It is an interprofessional specialty, primarily aiming to improve quality of care for cancer patients and their families, from the time of diagnosis of malignant disease, over the continuum of cancer care, and extending after the patient's death to the period of bereavement to support the patient's family. There are various complex and frequently unmet needs of lung cancer patients and their families/caregivers, not only physical but also psychological, social, spiritual and cultural. Systematic monitoring of patients’ symptoms using validated questionnaires and patient-reported outcomes (PROs), on a regular basis, is highly encouraged and recommended in recent guidelines on the role of PRO measures in the continuum of cancer clinical care. It improves patient–physician communication, physician awareness of symptoms, symptom control, patient satisfaction, health-related quality of life and cost-effectiveness. This implies that all treating physicians should improve their skills in communication with lung cancer patients/relatives and become more familiar with this multidimensional assessment, repeatedly screening patients for palliative care needs. Therefore, they should receive education and training to develop palliative care knowledge, skills and attitudes. This review is dedicated to lung cancer palliative care essentials that should be within the competences of treating physicians, i.e. pneumologists/thoracic oncologists.

The Scotch whisky distiller has announced a major change

The concierge team at The Balmoral have helped raise awareness for a special event to raise money for charity in memory of Scotland legend Doddie Weir.

The site, on the shores of a famous Scottish loch, has been acquired for a luxury lodge development

Some extremely fresh vintage workwear that I bought for entirely practical reasons aside, I’m not exactly a fashion person. I have nobody to impress most days but my cat, and the only item of clothing she appears to have an opinion on is my Oodie, which is very comfortable for both of us and also smells like a chicken shop, which I imagine is more pleasant for her than me.

This aside, I found myself taking a whole bunch of Dragon Age: The Veilguard screenshots as I played just to capture the RPG’s various outfits. They are ridiculous. Incredibly intricate and detailed, as well as being obscenely impractical for the most part. I do not like any of them in the sense I would wear them, but I like all of them in the sense that they display artists allowed to run free like caffeinated weasels and indulge their every whim.

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Enshrouded has received what developers Keen Games are calling the survival game's "most sizable" update yet, sizable being an appropriate word for mountains. Expect a new playable area, the Alabaneve Summits, with its own enemies, resources, non-threatening wildlife and quests. The maximum character level has risen to 35! There are new townsfolk to find and place in your poorly built houses! You can tame animals, and make them live in poorly built houses too! You can get hypothermia!

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HARI SREENIVASAN: Let’s turn to the continuing fallout and reaction to the Harvey Weinstein story.

Yesterday, Weinstein resigned from the board of his production company following numerous revelations of sexual harassment and several allegations of assault.

More than three dozen women have said Weinstein harassed them. While Weinstein has admitted to behaving inappropriately, he has said he didn’t physically assault anyone.

One of those women is Katherine Kendall. She was a 23-year-old actress who met Weinstein in 1993. She alleges that he invited her to his apartment in New York, where, she says, he took off his clothes and asked for a massage.

As other actresses began coming forward about their painful experiences, she also went public with her own story.

She joins me now from Los Angeles.

First, thanks for joining us.

And I don’t want to relive something that’s painful for you, but you are taking a public stance on it.

For people who don’t know your story, what happened?

KATHERINE KENDALL, Actress/ Photographer: Well, I was you know, a young actress, and I had had a formal meeting at the Miramax office earlier that day.

And then, at the end of the meeting, which I thought went really well, he invited me to come to screenings. He said: “Welcome to the Miramax family. You know, come to premieres, screenings, et cetera. In fact, there’s one this afternoon. Would you like to come?”

And I said, “Sure.”

And I ended up going to see a movie with him. It ended up just being a movie, not a screening, but the film “Red Rock West.” And, you know, that’s right when I had this sort of sinking feeling that something wasn’t going right.

And then, after the movie, we walked for a few blocks. And he said he needed to go up to his apartment to get something, and would I just come with him real quick? And I sort of said no, and we went back and forth on that for a minute. It was sort of a negotiation with him always, trying to sort of stand my ground, but then be convinced it was OK.

I did go into his apartment. Once there, we talked for a long time about art and movies. And I felt like he was treating me like an intellect.

And I felt like the meeting was going really well, and sort of continued. I didn’t feel unsafe once I was in there. And, at one point, then, he got up to go to the bathroom. And he came back in a robe and asked me to give him a massage.

And I was extremely uncomfortable. And I was like, oh, God, no, I’m not comfortable with that. And we went back and forth on that.

And then he went back to the bathroom again, and came back this time completely naked. And, you know, that changed it entirely for me, too. It just took it to the next place. It was completely disorienting. And I was scared, you know? I was really scared.

And then it became sort of a cat-and-mouse game of, like, how am I going to get out of there?

And I’m — it’s hard to make sense of what someone is trying to do to you when they’re fully naked, and they’re…

HARI SREENIVASAN: Yes.

KATHERINE KENDALL: You know, I’m 105 pounds. He’s a large man standing between me and the door.

And, I mean, I felt very resolute, like, I will definitely get out of here somehow. But I’m not — I’m not sure — I’m not sure what’s going to happen here. You know, a lot was going through my head.

And he said, well, if you won’t give me a massage, will you at least show me your breasts? And it was just — you know, it was, all in all, an extremely humiliating experience for me.

And even though I got away, I felt like something had still — like something horrible had just happened to me.

HARI SREENIVASAN: You know, in the immediate aftermath, did you tell someone about it? Because you have said before that you felt ashamed…

KATHERINE KENDALL: I did.

HARI SREENIVASAN: … even though you were the victim.

KATHERINE KENDALL: I did.

It’s really interesting how that happens. And I think — you know, I’m older now, and I have done some work on myself. And I have learned that a lot of people feel that way.

It’s — it’s not — it wasn’t just me. But the just me feeling that this is my fault, this must have only happened to me, there’s something wrong with me, is so common when someone perpetrates against you.

HARI SREENIVASAN: What were the…

KATHERINE KENDALL: And I did. I told my mom.

And I told some good friends. But, you know, one of the things that happened was, I didn’t want them to tell anybody. You know, people wanted to help me, but they didn’t know how, and I didn’t want them to try too hard, because I didn’t want it to backlash.

I was scared. And I think that it’s important to remember that we don’t really come from a culture that supports women in talking about sexual harassment, in my — in my experience, that is. And, you know, I just haven’t felt like it was something I was going to get support on…

HARI SREENIVASAN: You know, how long…

KATHERINE KENDALL: … in the bigger picture.

HARI SREENIVASAN: Yes.

How long did this feeling last? Or, I guess, what are the longer-term ripple effects here? Did it shake your confidence in your abilities?

KATHERINE KENDALL: I think it did. I think it did. I think it did.

I think it made me feel like, wow, you know, that was a wash. He wasn’t interested at all in what I had to say, or, you know, he didn’t see any talent there or intellect there. He was assessing the situation the whole time for something else.

And I think that — that did hurt. You know, I wish it didn’t.

HARI SREENIVASAN: Yes.

KATHERINE KENDALL: But he had produced so many movies that I thought were wonderful. And it was — it’s hard when someone has made art that you love, and how do you stay attached to liking their art, but feeling conflicted about them?

And, yes, I think it does have long-term effects. I think you tuck it away. And then, for me, also, I realized that it came back when I would see his name or see him in person. I would start to sort of tremble all over again.

I mean, I wouldn’t think about him on a daily basis or anything for years, and then I would see him, and I would think, oh, I don’t feel well. I got to get out of here.

HARI SREENIVASAN: Right.

KATHERINE KENDALL: You know, it would bring up so much emotion.

And the most recent one was the woman in New York, the Italian model. I felt so, so enraged when I saw what happened there, and that they sort of — the police had him, and that then he got away. And then she was being dragged through the press as somebody who just, you know, wanted a payout, et cetera.

HARI SREENIVASAN: You know, in the wake of that, there was — a friend of yours had tweeted, “At some point, all the women who have been afraid to speak out about Harvey Weinstein are going to have to hold hands and jump.” This was back in 2015.

And from your Twitter account, you said, “Agreed.”

It seemed like you almost had the opportunity to come forward.

What made you want to come forward now? Has this become a turning point in the industry?

KATHERINE KENDALL: This is a turning point. It’s a turning point.

There are so many times when I thought about it, and then felt like — there were times when I thought about it and said, well, I have nothing to lose, I will just do it. And then I thought, I — I just didn’t have the strength or the courage yet.

And I think somebody like Jodi Kantor doing the story for The New York Times, the fact that she thought it was a story at all was startling to me and made me feel like, wow, something is going to be done.

And I knew she had told me — I mean, they were looking for women that this had happened to, because they’d been hearing rumors for so long that it happened to so many people. And she had told me other people were coming out.

And I thought, I can’t — when I watched Rose McGowan or any of the other actresses come forward, I just — or Ashley Judd — I just thought, they look strong to me, and I don’t want to be the one that stays silent.

HARI SREENIVASAN: Well, Katherine Kendall…

KATHERINE KENDALL: I want to stand beside them.

HARI SREENIVASAN: Katherine Kendall, thank you very much for speaking with us.

And, hopefully, there are other people that are empowered by you coming forward.

KATHERINE KENDALL: I hope so. Thank you.

The post Escaping Harvey Weinstein was a ‘cat-and-mouse game,’ says Katherine Kendall appeared first on PBS NewsHour.

In a basement beneath City St George's, University of London, senior NATO leaders watch on as four research teams demonstrate the latest in AI-controlled, autonomous drone technolo0gy

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In a recent study led by Professor Xin Li and Dr. Yanlong Guo of the Institute of Tibetan Plateau Research, Chinese Academy of Sciences, researchers analyze how scientific research is evolving through the power of big data and artificial intelligence (AI). The paper discusses how the traditional "correlation supersedes causation" model is being increasingly challenged by new "data-intensive scie