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Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies1. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leading to dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in PDAC2, but their diversity has prevented therapeutic exploitation. Here we combined single-cell and spatial genomics with functional experiments to unravel macrophage functions in pancreatic cancer. We uncovered an inflammatory loop between tumour cells and interleukin-1β (IL-1β)-expressing TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E2(PGE2) and tumour necrosis factor (TNF). Physical proximity with IL-1β+TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatic tumorigenesis and led to persistent transcriptional changes associated with disease progression and poor outcomes for patients. Blocking PGE2or IL-1β activity elicited TAM reprogramming and antagonized tumour cell-intrinsic and -extrinsic inflammation, leading to PDAC control in vivo. Targeting the PGE2–IL-1β axis may enable preventive or therapeutic strategies for reprogramming of immune dynamics in pancreatic cancer.

Serious neurologic illnesses are associated with significant palliative care (PC) needs, including symptom management, complex decision-making, support for caregivers, and end-of-life care. While all neurologists are responsible for the provision of primary PC, there is an increasing need for trained neurologists with expertise in palliative medicine to manage refractory symptoms, mitigate conflict around goals of care, and provide specialized end-of-life care. This has led to the emergence of neuropalliative care (NPC) as a subspecialty. There are different ways to acquire PC skills, incorporate them into one's neurology practice, and develop a neuropalliative carer. We interviewed 3 leaders in the field of NPC, Dr. Robert Holloway, Dr. Jessica McFarlin, and Dr. Janis Miyasaki, who are all neurologists with different subspecialties and training pathways working in academic centers. They share their career paths, their advice for neurology trainees interested in pursuing a career in NPC, and their thoughts on the future of the field.

Background: Indirect evidence suggests that optimal vitamin D status is achieved with a serum 25-hydroxyvitamin D [25(OH)D] concentration >75 nmol/L. Objective: We aimed to determine the intake of vitamin [D.sub.3] needed to raise serum 25(OH)D to >75 nmol/L. Design: The design was a 6-mo, prospective, randomized, double-blinded, double-dummy, placebo-controlled study of vitamin [D.sub.3] supplementation. Serum 25(OH)D was measured by radioimmunoassay. Vitamin [D.sub.3] intake was adjusted every 2 mo by use of an algorithm based on serum 25(OH)D concentration. Results: A total of 138 subjects entered the study. After 2 dose adjustments, almost all active subjects attained concentrations of 25(OH)D >75 nmol/L, and no subjects exceeded 220 nmol/L. The mean ([+ or -] SD) slope at 9 wk [defined as 25(OH)D change/baseline dose] was 0.66 [+ or -] 0.35 (nmol/L)/([micro]g/d) and did not differ statistically between blacks and whites. The mean daily dose was 86 [micro]g (3440 IU). The use of computer simulations to obtain the most participants within the range of 75-220 nmol/L predicted an optimal daily dose of 115 [micro]g/d (4600 IU). No hypercalcemia or hypercalciuria was observed. Conclusions: Determination of the intake required to attain serum 25(OH)D concentrations >75 nmol/L must consider the wide variability in the dose-response curve and basal 25(OH)D concentrations. Projection of the dose-response curves observed in this convenience sample onto the population of the third National Health and Nutrition Examination Survey suggests a dose of 95 [micro]g/d (3800 IU) for those above a 25 (OH)D threshold of 55 nmol/L and a dose of 125 [micro]g/d (5000 IU) for those below that threshold.

Dermatomyositis (DM) is an autoimmune myopathy characterized by proximal muscle weakness and distinct skin findings. DM is associated with an increased risk of malignancy in adults. We describe a case of dermatomyositis with unusually severe oropharyngeal dysphagia and respiratory muscle weakness on presentation, who was found to have underlying metastatic prostate cancer. Prostate cancer is uncommonly associated with DM. The patient tested positive for antitranscription intermediate family-1 (anti-TIF-1, also known as anti-p155/410) antibodies, which are linked to malignancy-associated DM in adults and are associated with dysphagia and more severe cutaneous findings.

There is growing recognition that neutrophils play an important role in cancer initiation, progression and metastasis. Although they are typically characterized as short-lived effector cells, neutrophils have been shown to acquire immunosuppressive and pro-tumorigenic functions that promote tumor progression and escape. As such, inhibition of their function or depletion of neutrophils are being explored as potential cancer therapies. However, growing evidence of neutrophil diversification in cancer and their potential anti-tumor roles raise many unresolved questions. Here, we review recent advances that address the definition, origin and function of neutrophils in cancer, and elaborate on obstacles that make the study of neutrophils challenging. We envision that this review will provide the groundwork for focused design of therapeutics that will specifically target “tumorreprogrammed” neutrophils while sparing normal neutrophils to improve patient outcomes.

Spring heralds the start of New York City's tourist season for 1998, which is expected to be another banner year for the Big Apple. Occupancy in 1997 reached a high […]

Globalization and new markets are creating more opportunities for corporate travel agencies In contrast to the commission caps nightmare of 1995, this past year was a relatively quiet one for […]

With an objective eye turned toward its problems, the car rental industry is taking measures to strengthen its position Strained finances and the pressures they cause were the hallmark of […]

Intestinal stromal cells are known to modulate the propagation and differentiation of intestinal stem cells1,2. However, the precise cellular and molecular mechanisms by which this diverse stromal cell population maintains tissue homeostasis and repair are poorly understood. Here we describe a subset of intestinal stromal cells, named MAP3K2-regulated intestinal stromal cells (MRISCs), and show that they are the primary cellular source of the WNT agonist R-spondin 1 following intestinal injury in mice. MRISCs, which are epigenetically and transcriptomically distinct from subsets of intestinal stromal cells that have previously been reported3–6, are strategically localized at the bases of colon crypts, and function to maintain LGR5+intestinal stem cells and protect against acute intestinal damage through enhanced R-spondin 1 production. Mechanistically, this MAP3K2 specific function is mediated by a previously unknown reactive oxygen species (ROS)–MAP3K2–ERK5–KLF2 axis to enhance production of R-spondin 1. Our results identify MRISCs as a key component of an intestinal stem cell niche that specifically depends on MAP3K2 to augment WNT signalling for the regeneration of damaged intestine.

New York State is the state for all seasons. And with spring finally here, there are plenty of outdoor activities for visitors to the Empire State to indulge in - […]

Whether you're at an airport lounge waiting to board a flight, checking in at a hotel or picking up a rental car, there's a very good chance the person standing […]

Clients looking for holiday hotel getaways will find plenty to choose from in Manhattan New York abounds this season with special hotel packages and discounted rates for clients spending the […]

ASTA President Mike Spinelli has become something of a weatherman in his effort to enroll more members from corporate agencies. Although many mega-agencies have the resources to stand alone, Spinelli […]

The bombshell dropped in February 1995, when six major carriers, led by Delta Air Lines, capped commissions on domestic air tickets at $50 each. At the time, doom-sayers were predicting […]

Renovated theaters, theme restaurants and an improved quality of life have revived the area First it was Mickey Mouse and his Disney entourage, now it's Bugs Bunny and his gang […]

Management practices in early-stage (I/II) follicular lymphoma (FL) are variable and include radiation (RT), systemic therapy, or combined modality therapy (CMT). There is a paucity of data regarding maintenance rituximab in this cohort. We conducted an international retrospective study of patients with newly diagnosed early-stage FL staged with positron emission tomography (PET)–computed tomography and bone marrow biopsy. Three hundred sixty-five patients (stage I, n = 221), median age 63 years, treated from 2005-2017 were included, with a median follow-up of 45 months. Management included watchful waiting (WW; n = 85) and active treatment (n = 280). The latter consisted of RT alone (n = 171) or systemic therapy (immunochemotherapy [n = 63] or CMT [n = 46]). Forty-nine systemically treated patients received maintenance rituximab; 72.7% of stage I patients received RT alone, compared to 42.6% with stage II (P < .001). Active therapies yielded comparable overall response rates (P = .87). RT alone and systemic therapy without maintenance rituximab yielded similar progression-free survival (PFS) (hazard ratio [HR], 1.32; 95% confidence interval [CI], 0.77-2.34; P = .96). Maintenance rituximab improved PFS (HR, 0.24; 95% CI, 0.095-0.64; P = .017). The incidence of transformation was lower with systemic therapy compared to RT or WW (HR, 0.20; 95% CI, 0.070-0.61; P = .034). Overall survival was similar among all practices, including WW (P = .40). In the largest comparative assessment of management practices in the modern era, variable practices each resulted in similar excellent outcomes. Randomized studies are required to determine the optimal treatment in early-stage FL.

When smaller travel agencies become part of a bigger entity, both parties can benefit Melissa Ng Changes in the travel industry have spurred many to look at different ways to […]

A specialist in Europe's fastest growing destination, CIE Tours has new products to meet the demand for Ireland and Britain In the late 1980s, CIE Tours, an operator specializing in […]

Hotels and resorts are providing more and more options for on-the-road executives Melissa Ng The booming economy ensures that the pace for business travelers is not likely to let up […]

Melissa Ng Business travelers and vacationers alike want to stretch their travel dollars. To help them, card companies offer destination-specific promotions with room upgrades and discounts on meals, sightseeing and […]

New York's convention bureau is looking at new ways to finance Big Apple promotions She may have been at the helm for only a month, but that didn't stop Fran […]

Hotel chains are providing service and reward programs to make life easier for meeting planners A new trend is sweeping the meetings market, and hotels across the U.S. are responding […]

McCord Travel Management now has a renewed focus on cross-selling leisure travel Chicago-based McCord Travel Management planted the seeds of growth back in 1995, when it acquired New York-based Zenith […]

The New York Convention & Visitors Bureau is spreading its promotional wings The boom in New York's tourism continues, but Fran Reiter, the new president and CEO of the New […]

New York has started preparations to greet the new millennium - whenever it starts While the debate continues over whether the new millennium officially begins in 2000 or one year […]

Activities abound in the Empire State for winter enthusiasts, from skiing to seasonal festivals Winter activities in New York include events on and off the slopes. There are more than […]

World Travel Specialists Group shows that better service can lead to a bigger payoff Would you drive into New York City from New Jersey on a Saturday to get an […]

Just when corporate travel agents thought it was safe to swim in the post-cap world, they had to deal with a second spate of cutbacks in September. The blow sent […]

They may not be holding rallies and demonstrating outside airline offices, but travel managers are certainly unhappy about rising business air fares. A survey released by the National Business Travel […]

Agents looking for new ways to build their business should explore incentive travel As the reality of commission cuts sink in, agents need to evaluate other ways to help them […]

Visitors are finding they can effectively explore the heart of the city using their soles The beauty of New York City lies in its history, energy and vibrancy, and there […]

As summer's lush green leaves turn golden and red, areas throughout New York start gearing up for fall festivals. But such celebrations aren't the only way to commemorate autumn in […]

Relief is in sight for visitors trying to get a hotel room in New York City. A number of new hotel developments and renovations are in the works. The additional […]

Many of New York City's must-see attractions for first-time visitors - including the Statue of Liberty, Battery Park City, Wall Street and the World Trade Center - are in lower […]

NEW YORK - Ruling that Omega World Travel "acted to protect the welfare of its customers" in selling discounted TWA tickets, a Missouri Circuit Court judge in St. Louis dismissed […]

With summer in high gear, visitors to the Big Apple will want to find ways to escape the steamy heat and humidity. One way for them to do so is […]

ST. LOUIS - The voice of technology was loud and clear last week at the 29th Annual National Business Travel Association (NBTA) convention, where several companies announced they are developing […]