Improved survival for dose-intensive chemotherapy in primary mediastinal B-cell lymphoma: a systematic review and meta-analysis of 4,068 patients.

Primary mediastinal B-cell lymphoma (PMBCL) is a distinct clinicopathologic entity. Currently, there is a paucity of randomized prospective data to inform on optimal front-line chemoimmunotherapy (CIT) and use of consolidative mediastinal radiation (RT). To assess if distinct CIT approaches are associated with disparate survival outcomes, we performed a systematic review and meta-analysis comparing dose-intensive (DI-CIT) versus standard CIT for the front-line treatment of PMBCL. Standard approach (S-CIT) was defined as R-CHOP-21/CHOP-21, with or without RT. DI-CIT were defined as regimens with increased frequency, dose, and/or number of systemic agents. We reviewed data on 4,068 patients (2,517 DI-CIT; 1,551 S-CIT) with a new diagnosis of PMBCL. Overall survival for DI-CIT patients was 88% (95% CI: 85-90) compared to 80% for the S-CIT cohort (95% CI: 74-85). Meta-regression revealed an 8% overall survival (OS) benefit for the DI-CIT group (P<0.01). Survival benefit was maintained when analyzing rituximab only regimens; OS was 91% (95% CI: 89-93) for the rituximab-DI-CIT arm compared to 86% (95% CI: 82-89) for the R-CHOP-21 arm (P=0.03). Importantly, 55% (95% CI: 43-65) of the S-CIT group received RT compared to 22% (95% CI: 15-31) of DI-CIT patients (meta-regression P<0.01). To our knowledge, this is the largest meta-analysis reporting efficacy outcomes for the front-line treatment of PMBCL. DI-CIT demonstrates a survival benefit, with significantly less radiation exposure, curtailing long-term toxicities associated with radiotherapy. As we await results of randomized prospective trials, our study supports the use of dose-intensive chemoimmunotherapy for the treatment of PMBCL.

Stimuli-Responsive Polymers for Engineered Emulsions.

Emulsions are complex. Dispersing two immiscible phases, thus expanding an interface, requires effort to achieve and the resultant dispersion is thermodynamically unstable, driving the system toward coalescence. Furthermore, physical instabilities, including creaming, arise due to presence of dispersed droplets of different densities to a continuous phase. Emulsions allow the formulation of oils, can act as vehicles to solubilize both hydrophilic and lipophilic molecules, and can be tailored to desirable rheological profiles, including "gel-like" behavior and shear thinning. The usefulness of emulsions can be further expanded by imparting stimuli-responsive or "smart" behaviors by inclusion of a stimuli-responsive emulsifier, polymer or surfactant. This enables manipulation like gelation, breaking, or aggregation, by external triggers such as pH, temperature, or salt concentration changes. This platform generates functional materials for pharmaceuticals, cosmetics, oil recovery, and colloid engineering, combining both smart behaviors and intrinsic benefit of emulsions. However, with increased functionality comes greater complexity. This review focuses on the use of stimuli-responsive polymers for the generation of smart emulsions, motivated by the great adaptability of polymers for this application and their efficacy as steric stabilizers. Stimuli-responsive emulsions are described according to the trigger used to provide the reader with an overview of progress in this field.

Testosterone therapy and cancer risks among men in the SEER-Medicare linked database.

BACKGROUND: We examined associations between two forms of testosterone therapy (TT) and risks of seven cancers among men. METHODS: SEER-Medicare combines cancer registry data from the Surveillance, Epidemiology, and End Results programme with Medicare claims. Our population-based case-control study included incident cancer cases diagnosed between 1992-2015: prostate (n = 130,713), lung (n = 105,466), colorectal (n = 56,433), bladder (n = 38,873), non-Hodgkin lymphoma (n = 17,854), melanoma (n = 14,241), and oesophageal (n = 9116). We selected 100,000 controls from a 5% random sample of Medicare beneficiaries and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: TT was associated with lower risk of distant-stage prostate cancer (injection/implantation OR = 0.72, 95% CI: 0.60-0.86; topical OR = 0.50, 95% CI: 0.24-1.03). We also observed inverse associations for distant-stage colorectal cancer (injection/implantation OR = 0.75, 95% CI: 0.62-0.90; topical OR = 0.11, 95% CI: 0.05-0.24). Risks of distant-stage colorectal and prostate cancers decreased with time after initiating TT by injection/implantation. By contrast, TT was positively associated with distant-stage melanoma (injection/implantation OR = 1.70, 95% CI: 1.37-2.11). TT was not associated with bladder cancer, oesophageal cancer, lung cancer or non-Hodgkin lymphoma. CONCLUSION: TT was inversely associated with distant-stage prostate and colorectal cancers but was positively associated with distant-stage melanoma. These observations may suggest an aetiologic role for TT or the presence of residual confounding.

Novel determinants of cell size homeostasis in the opportunistic yeast Candida albicans.

The basis for commitment to cell division in late G1 phase, called Start in yeast, is a critical but still poorly understood aspect of eukaryotic cell proliferation. Most dividing cells accumulate mass and grow to a critical cell size before traversing the cell cycle. This size threshold couples cell growth to division and thereby establishes long-term size homeostasis. At present, mechanisms involved in cell size homeostasis in fungal pathogens are not well described. Our previous survey of the size phenome in Candida albicans focused on 279 unique mutants enriched mainly in kinases and transcription factors (Sellam et al. PLoS Genet 15:e1008052, 2019). To uncover novel size regulators in C. albicans and highlight potential innovation within cell size control in pathogenic fungi, we expanded our genetic survey of cell size to include 1301 strains from the GRACE (Gene Replacement and Conditional Expression) collection. The current investigation uncovered both known and novel biological processes required for cell size homeostasis in C. albicans. We also confirmed the plasticity of the size control network as few C. albicans size genes overlapped with those of the budding yeast Saccharomyces cerevisiae. Many new size genes of C. albicans were associated with biological processes that were not previously linked to cell size control and offer an opportunity for future investigation. Additional work is needed to understand if mitochondrial activity is a critical element of the metric that dictates cell size in C. albicans and whether modulation of the onset of actomyosin ring constriction is an additional size checkpoint.

Association between psoriatic disease and lifestyle factors and comorbidities: cross-sectional analysis and Mendelian randomization.

OBJECTIVES: To examine associations between PsA and psoriasis vs lifestyle factors and comorbidities by triangulating observational and genetic evidence. METHODS: We analysed cross-sectional data from the UK Biobank (1836 PsA, 8995 psoriasis, 36 000 controls) to describe the association between psoriatic disease and lifestyle factors (including BMI and smoking) and 15 comorbidities [including diabetes and coronary artery disease (CAD)] using logistic models adjusted for age, sex and lifestyle factors. We applied bidirectional Mendelian randomization (MR) to genome-wide association data (3609 PsA and 7804 psoriasis cases, up to 1.2 million individuals for lifestyle factors and 757 601 for comorbidities) to examine causal direction, using the inverse-variance weighted method. RESULTS: BMI was cross-sectionally associated with risk of PsA (OR 1.31 per 5 kg/m2 increase; 95% CI 1.26, 1.37) and psoriasis (OR 1.23; 1.20, 1.26), with consistent MR estimates (PsA OR 1.38; 1.14, 1.67; psoriasis OR 1.36; 1.18, 1.58). In both designs, smoking was more strongly associated with psoriasis than PsA. PsA and psoriasis were cross-sectionally associated with diabetes (OR 1.35 and 1.39, respectively) and CAD (OR 1.56 and 1.38, respective). Genetically predicted glycated haemoglobin (surrogate for diabetes) increased PsA risk (OR 1.18 per 6.7 mmol/mol increase; 1.02, 1.36) but not psoriasis. Genetic liability to PsA (OR 1.05; 1.003, 1.09) and psoriasis (OR 1.03; 1.001, 1.06) were associated with increased risk of CAD. CONCLUSION: Observational and genetic evidence converge to suggest that BMI and glycaemic control are associated with increased psoriatic disease risk, while psoriatic disease is associated with increased CAD risk. Further research is needed to understand the mechanism of these associations.

Number of CAG repeats and mortality in middle aged and older men.

DESIGN: The androgen receptor (AR) mediates peripheral effects of testosterone. Previous data suggests an association between the number of CAG repeats in exon-1 of the AR gene and AR transcriptional activity. The aim of this analysis was to determine the association between the number of AR CAG repeats and all-cause mortality in men and the influence of testosterone level on the association. PATIENTS AND MEASUREMENTS: Follow-up data to 27 January 2018 were available for men aged 40-79 years recruited across six countries of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios (HR)/95% confidence intervals (CI). RESULTS: One thousand nine hundred and seventy-seven men were followed up. Mean baseline age was 60 ± 11.1 years. Mean duration of follow-up was 12.2 years. At follow up 25.1% of men had died. CAG repeat length ranged from 6 to 39, with the highest proportion of CAG repeat number at 21 repeats (16.4%). In a multivariable model, compared to men with 22-23 AR CAG repeats: for men with <22 and >23 AR CAG HR, 95% CI for mortality were, <22 CAG repeats 1.17 (0.93-1.49) and >23 CAG repeats 1.14 (0.88-1.47). In a post-hoc analysis, the association was significant for men in the lowest tertile of baseline testosterone (<14.2 nmol/L) with >23 CAG repeats: in the adjusted model for <22 and >23 CAG repeats, respectively, 1.49 (0.97-2.27) and 1.68 (1.06-2.67) versus 22-23 repeats. CONCLUSIONS: Our European-wide cohort data overall found no association of androgen receptor CAG repeat number and mortality in men. However, post hoc analysis suggested that an association might be present in men with lower baseline testosterone concentrations, which merits further investigation.

Branched copolymer surfactants impart thermoreversible gelation to LAPONITE® gels.

This investigation seeks to integrate LAPONITE® clay gels with thermoresponsive branched copolymer surfactants (BCSs) to develop advanced functional materials with temperature-induced sol-gel behaviour. It is known that a diverse range of molecules adsorb strongly to clays which may be used to control liberation of the species in healthcare applications, and as such the development of polymer/clay hybrid materials which can add function to the native clay behaviour are of great interest. BCS were synthesised with a structure that encompasses poly(ethylene glycol)methacrylate (PEGMA), ethylene glycol dimethacrylate (EGDMA), and dodecanethiol (DDT), conferring versatile and tuneable thermoresponsive attributes. Systematic modulation of the monomer : DDT/initiator ratio was used to facilitate the synthesis of BCS architectures spanning a range of molecular weights. Through application of small-amplitude oscillatory shear (SAOS) rheology and small-angle neutron scattering (SANS) in conjunction with controlled temperature variations, the sol-gel transition dynamics of these nanocomposite materials were elucidated. Complementary insights into the mechanisms underpinning this transition and temperature-induced alterations in the constituents are gleaned through the utilization of SANS techniques employing contrast-matching methodologies to mitigate clay and polymer scattering interference. It is found that heating systems from room- to body- temperature induces self-assembly of BCS in the bulk aqueous phase with concurrent structuration of clay in gel-forming samples with lower number average molecular weight (Mn). SANS study unpicks this phenomenon to find that gelation occurs with concurrent aggregation of BCS in the bulk, inducing clay-clay interactions only in lower Mn BCS systems with large nanoaggregates.

Does testosterone influence the association between sleep and frailty in men: results from the European Male Aging Study.

BACKGROUND: Previous studies have suggested an association between sleep disturbance and frailty. The mechanism is unknown, although it has been suggested that hormonal factors may play a role. METHODS: The aim was to determine the association between sleep duration, sleep quality and frailty, and to determine whether testosterone influenced this association. Males aged 40-79 years were recruited from eight European centres to the European Male Aging Study (EMAS). Subjects completed an interviewer-assisted questionnaire including questions regarding sleep quality and duration. Sleep quality was scored 0-20 and categorised as 0-4, 5-9, 10-14, and 15-20, with higher scores indicating poorer quality. A 39-component frailty index (FI) was constructed. Total testosterone levels were measured. The association between sleep duration, sleep quality and the FI was assessed using negative binomial regression, with adjustment for putative confounders including testosterone level. RESULTS: Two thousand three hundred ninety-three participants contributed data to the analysis. The mean age was 63.3 years and mean sleep duration was 7.01 h. The mean frailty index was 0.15. Mean testosterone levels declined with decreasing sleep quality. After adjustment, compared to those with a sleep score of 0-4, the FI was 57% (95% CI 38%, 78%) higher among those with a sleep score of 15-20. After adjustment compared to those with normal sleep duration (6-9 h), those with a short (< 6 h) and long (≥ 9 h) sleep duration had a 16% (95% CI 6%, 28%) and 11% (95% CI 0%, 23%) higher FI, respectively. Adjustment for testosterone did not influence the strength of either association. CONCLUSION: Frailty is associated with impaired sleep quality and sleep duration. The association cannot, however, be explained by variation in testosterone levels.

Lessons from assembling a microbial natural product and pre-fractionated extract library in an academic laboratory.

Microbial natural products are specialized metabolites that are sources of many bioactive compounds including antibiotics, antifungals, antiparasitics, anticancer agents, and probes of biology. The assembly of libraries of producers of natural products has traditionally been the province of the pharmaceutical industry. This sector has gathered significant historical collections of bacteria and fungi to identify new drug leads with outstanding outcomes-upwards of 60% of drug scaffolds originate from such libraries. Despite this success, the repeated rediscovery of known compounds and the resultant diminishing chemical novelty contributed to a pivot from this source of bioactive compounds toward more tractable synthetic compounds in the drug industry. The advent of advanced mass spectrometry tools, along with rapid whole genome sequencing and in silico identification of biosynthetic gene clusters that encode the machinery necessary for the synthesis of specialized metabolites, offers the opportunity to revisit microbial natural product libraries with renewed vigor. Assembling a suitable library of microbes and extracts for screening requires the investment of resources and the development of methods that have customarily been the proprietary purview of large pharmaceutical companies. Here, we report a perspective on our efforts to assemble a library of natural product-producing microbes and the establishment of methods to extract and fractionate bioactive compounds using resources available to most academic labs. We validate the library and approach through a series of screens for antimicrobial and cytotoxic agents. This work serves as a blueprint for establishing libraries of microbial natural product producers and bioactive extract fractions suitable for screens of bioactive compounds. ONE-SENTENCE SUMMARY: Natural products are key to discovery of novel antimicrobial agents: Here, we describe our experience and lessons learned in constructing a microbial natural product and pre-fractionated extract library.

Time to negative throat culture following initiation of antibiotics for pharyngeal group A Streptococcus: a systematic review and meta-analysis up to October 2021 to inform public health control measures.

BackgroundPublic health guidance recommending isolation of individuals with group A streptococcal (GAS) infection or carriage for 12-24 h from antibiotic initiation to prevent onward transmission requires a strong evidence base.AimTo estimate the pooled proportion of individuals who remain GAS culture-positive at set intervals after initiation of antibiotics through a systematic literature review (PROSPERO CRD42021290364) and meta-analysis.MethodsWe searched Ovid MEDLINE (1946-), EMBASE (1974-) and Cochrane library. We included interventional or observational studies with ≥ 10 participants reporting rates of GAS throat culture positivity during antibiotic treatment for culture-confirmed GAS pharyngitis, scarlet fever and asymptomatic pharyngeal GAS carriage. We did not apply age, language or geographical restrictions.ResultsOf 5,058 unique records, 43 were included (37 randomised controlled studies, three non-randomised controlled trials and three before-and-after studies). The proportion of individuals remaining culture-positive on day 1, day 2 and days 3-9 were 6.9% (95% CI: 2.7-16.8%), 5.4% (95% CI: 2.1-13.3%) and 2.6% (95% CI: 1.6-4.2%). For penicillins and cephalosporins, day 1 positivity was 6.5% (95% CI: 2.5-16.1%) and 1.6% (95% CI: 0.04-42.9%), respectively. Overall, for 9.1% (95% CI: 7.3-11.3), throat swabs collected after completion of therapy were GAS culture-positive. Only six studies had low risk of bias.ConclusionsOur review provides evidence that antibiotics for pharyngeal GAS achieve a high rate of culture conversion within 24 h but highlights the need for further research given methodological limitations of published studies and imprecision of pooled estimates. Further evidence is needed for non-beta-lactam antibiotics and asymptomatic individuals.

Quantifying Asymmetry and Performance of Lower Limb Mechanical Muscle Function in Varsity Athletes-Using Non-Countermovement Jumps.

ABSTRACT: Stadnyk, M, Sepehri, M, Cook, M, Adeeb, S, and Westover, L. Quantifying asymmetry and performance of lower limb mechanical muscle function in varsity athletes-using non-countermovement jumps. J Strength Cond Res 37(1): 98-106, 2023-The ability to automatically quantify jump performance and lower limb muscle function in athletes would be beneficial for both training and rehabilitation purposes. Countermovement jumps (CMJs) and non-CMJs (NCMJs) are simple, quick, and require relatively inexpensive equipment to effectively and reliably monitor lower limb function. In a previous study, CMJ characteristics were assessed across different varsity sports. This study is a follow-up study to incorporate NCMJs into assessing jump characteristics of the same sports and investigate the additional information provided by the complementary jump type. The main objective of this study was to look at a means of quantifying the lower limb mechanical muscle function automatically to provide information for rehabilitation and performance purposes in athletes of specific sports. Male and female varsity athletes from 4 different sports completed 5 trials of an NCMJ on dual force plates. An analysis program was developed using Wolfram Mathematica to analyze force-time jump data. Various parameters of interest were generated, including peak force, force-time curve shape classification, jump phase lengths, phase-specific kinetic impulse, asymmetry index, takeoff velocity, jump height, phase-specific center of mass displacements, and reactive strength index modified. Results obtained indicate that similar jump characteristics to the CMJ study can be quantified, which can be used for performance enhancement or injury rehabilitation. Additional data found, such as the ability of an athlete to hold a steady squat during an NCMJ, could also be meaningful in aiding trainers to design programs tailored for athletes.

Sex disparities in the incidence of 21 cancer types: Quantification of the contribution of risk factors.

BACKGROUND: Cancer incidence is higher in men than in women at most shared anatomic sites for currently unknown reasons. The authors quantified the extent to which behaviors (smoking and alcohol use), anthropometrics (body mass index and height), lifestyles (physical activity, diet, medications), and medical history collectively explain the male predominance of risk at 21 shared cancer sites. METHODS: Prospective cohort analyses (n = 171,274 male and n = 122,826 female participants; age range, 50-71 years) in the National Institutes of Health-AARP Diet and Health Study (1995-2011). Cancer-specific Cox regression models were used to estimate male-to-female hazard ratios (HRs). The degree to which risk factors explained the observed male-female risk disparity was quantified using the Peters-Belson method. RESULTS: There were 26,693 incident cancers (17,951 in men and 8742 in women). Incidence was significantly lower in men than in women only for thyroid and gallbladder cancers. At most other anatomic sites, the risks were higher in men than in women (adjusted HR range, 1.3-10.8), with the strongest increases for bladder cancer (HR, 3.33; 95% confidence interval [CI], 2.93-3.79), gastric cardia cancer (HR, 3.49; 95% CI, 2.26-5.37), larynx cancer (HR, 3.53; 95% CI, 2.46-5.06), and esophageal adenocarcinoma (HR, 10.80; 95% CI, 7.33-15.90). Risk factors explained a statistically significant (nonzero) proportion of the observed male excess for esophageal adenocarcinoma and cancers of liver, other biliary tract, bladder, skin, colon, rectum, and lung. However, only a modest proportion of the male excess was explained by risk factors (ranging from 50% for lung cancer to 11% for esophageal adenocarcinoma). CONCLUSIONS: Men have a higher risk of cancer than women at most shared anatomic sites. Such male predominance is largely unexplained by risk factors, underscoring a role for sex-related biologic factors.

Mitochondrial Targeting and Imaging with Small Organic Conjugated Fluorophores: A Review.

The last decade has seen an increasingly large number of studies reporting on the development of novel small organic conjugated systems for mitochondrial imaging exploiting optical signal transduction pathways. Mitochondria are known to play a critical role in a number of key biological processes, including cellular metabolism. Importantly, irregularities on their working function are nowadays understood to be intimately linked to a range of clinical conditions, highlighting the importance of targeting mitochondria for therapeutic benefits. In this work we carry out an in-depth evaluation on the progress to date in the field to pave the way for the realization of superior alternatives to those currently existing. The manuscript is structured by commonly used chemical scaffolds and comprehensively covers key aspects factored in design strategies such as synthetic approaches as well as photophysical and biological characterization, to foster collaborative work among organic and physical chemists as well as cell biologists.

The Risk of Opportunistic Infections and the Role of Antibiotic Prophylaxis in Patients on Checkpoint Inhibitors Requiring Steroids.

BACKGROUND: Immune-related adverse events (irAEs) often require treatment with high-dose systemic steroids (SS) and other immunosuppressive agents (ISAs). NCCN Guidelines recommend prophylactic antibiotics for Pneumocystis jirovecii pneumonia (PJP) for patients receiving prolonged SS/ISAs. However, there is a paucity of evidence regarding the incidence of opportunistic infections (OIs) and non-OIs and the role of prophylactic antibiotics in patients on SS/ISAs for irAEs. METHODS: A retrospective analysis was conducted of patients treated using immune checkpoint inhibitor (ICI) therapy at 5 MedStar Health hospitals from January 2011 to April 2018. OIs were defined per the Infectious Diseases Society of America guidelines for the prevention and treatment of OIs in patients with HIV. The study cohort included patients who received ≥20 mg daily of a prednisone equivalent for ≥4 weeks to manage irAEs. RESULTS: The study cohort identified 112 (15%) of 758 total patients treated using ICIs. Baseline characteristics included the following: median age was 64 years, 74% (n=82) of patients were White, 89% (n=100) had an ECOG performance status ≤1, 61% (n=68) had melanoma, 19% (n=21) had non-small cell lung cancer, 45% (n=50) were treated using an anti-PD-(L)1 ICI, and 33% (n=37) were treated using an anti-PD-1/anti-CTLA-4 combination. The median starting SS dose was 100 mg of a prednisone equivalent, and 25% of patients required additional ISAs, with infliximab (n=15) and mycophenolate mofetil (n=9) being the most common. We found that 20% (n=22) of patients developed any infection, including 7% (n=8) with OIs (oral candidiasis [n=4], nondisseminated varicella zoster infection [n=2], PJP [n=1], and Listeria monocytogenes endophthalmitis [n=1]) and 13% (n=14) with non-OIs (most common: Clostridium difficile and pneumonia [n=5 each]). PJP prophylaxis with sulfamethoxazole/trimethoprim was given to 13% (n=14) patients, of whom 43% (n=6) developed OIs/non-OIs. CONCLUSIONS: Our study highlights the fundamental issues for patients on ICI therapy who require SS/ISAs for irAEs: the degree of immunosuppression and the relative risk of OI. We noted a low incidence of OIs overall and breakthrough infections despite PJP prophylaxis. We question whether PJP prophylaxis is efficacious or necessary. Prospective trials are required to answer these questions.

The number of androgen receptor CAG repeats and mortality in men.

INTRODUCTION: The androgen receptor (AR) mediates peripheral effects of testosterone. Evidence suggests that the number of CAG repeats in exon-1 of the AR gene negatively correlates with AR transcriptional activity. The aim of this analysis was to determine the association between CAG repeat number and mortality in men. METHODS: Men aged 40-79 years were recruited from primary care for participation in the UK arm of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios(HR)/95% confidence intervals (CI). RESULTS: 312 men were followed up. The mean baseline age was 59.5 years. At follow up, 85/312(27%) men had died. CAG repeat length ranged from 14 to 39, with the highest proportion of CAG repeat number at 21 repeats(16.4%). In a multivariable model, using men with CAG repeat numbers of 22-23 as the reference, men with a lower number of CAG repeats(<22) showed a trend for a higher mortality in the follow-up period (HR 1.46 (0.75, 2.81)) as did men with higher number of repeats (>23) (1.37 (0.65, 2.91)). CONCLUSION: Our data suggest that CAG repeat number may partially influence the risk of mortality in men. Further larger studies are required to quantify the effect.

Targeting The Tumor Microenvironment in Lymphomas: Emerging Biological Insights and Therapeutic Strategies.

PURPOSE OF REVIEW: This review aims to discuss recent advances in elucidating the tumor microenvironment (TME) in B lymphomas and resultant novel therapeutic development. RECENT FINDINGS: While tumor morphology, immunophenotype, and molecular profile are established factors that predict outcome and guide therapy, the prognostic impact of infiltrating, non-tumor cells is now emerging. This is simultaneously facilitating the development of new therapies that target non-tumor cells. The tumor microenvironment (TME) is a complex ecosystem composed of infiltrating cells and byproducts, extracellular matrix, and other non-cellular tissues. In lymphomas, our current understanding of the role of the TME is principally informed by studies in B-cell lineage diseases. As we improve our understanding of lymphoma biology, the importance of the impact of the non-tumor cell microenvironment is becoming more apparent. This lays the foundation for the investigation and development of novel therapies and combination strategies that target non-tumor cells and tumor cell/non-tumor cell interactions.

The impact of frailty on short-term mortality following primary total hip and knee arthroplasty due to osteoarthritis.

BACKGROUND: We determined the association between frailty and short-term mortality following total hip and knee arthroplasty (THA/TKA) for osteoarthritis and also the impact of THA/TKA on short-term mortality compared with a control population. METHODS: Frailty was assessed using a frailty index (categorised: fit, mild, moderate, severe frailty). The association between frailty and short-term mortality following THA/TKA was assessed using Cox regression. Mortality following THA/TKA was also compared with a control population with osteoarthritis but no previous THA/TKA, matched on year of birth, sex and quintile of index of multiple deprivation. RESULTS: A total of 103,563 cases who had a THA, 125,367 who had a TKA and matched controls contributed. Among those who had surgery, mortality increased with increasing frailty; adjusted hazard ratio (HR) (95% CI) at 30 days in severely frail versus fit: following THA, 2.85 (1.84, 4.39) and following TKA, 2.14 (1.29, 3.53). The predicted probability of 30-day mortality following THA/TKA varied by age, sex and frailty: following THA, from 0.05% among fit women aged 60-64 years to 6.55% among men with severe frailty aged ≥90 years. All-cause 30-day mortality was increased in fit cases following THA and TKA, respectively, versus fit controls (adjusted HR (95% CI), 1.60 (1.15, 2.21) and 2.98 (1.81, 4.89)), though not among cases with mild, moderate or severe frailty versus controls in the same frailty category. CONCLUSION: Short-term mortality increased with increasing frailty following THA/TKA. Comparison of mortality among cases and controls may be affected by a 'healthy surgery' selection effect.

The impact of frailty on patient-reported outcomes following hip and knee arthroplasty.

AIM: to determine the impact of frailty on patient-reported outcomes following hip and knee arthroplasty. METHODS: we used linked primary and secondary care electronic health records. Frailty was assessed using the electronic frailty index (categorised: fit, mild, moderate, severe frailty). We determined the association between frailty category and post-operative Oxford hip/knee score (OHS/OKS) using Tobit regression. We calculated the proportion of patients in each frailty category who achieved the minimally important change (MIC) in OHS (≥8 points) and OKS (≥7 points) and the proportion who reported a successful outcome (hip/knee problems either 'much better' or 'a little better' following surgery). RESULTS: About 42,512 people who had a hip arthroplasty and 49,208 who had a knee arthroplasty contributed data. In a Tobit model adjusted for pre-operative OHS/OKS, age, sex and quintile of index of multiple deprivation, increasing frailty was associated with decreasing post-operative OHS and OKS, respectively, ß-coefficient (95% CI) in severely frail versus fit, -6.97 (-7.44, -6.49) and - 5.88 (-6.28, -5.47). The proportion of people who achieved the MIC in OHS and OKS, respectively, decreased from 92 and 86% among fit individuals to 84 and 78% among those with severe frailty. Patient-reported success following hip and knee arthroplasty, respectively, decreased from 97 and 93% among fit individuals to 90 and 83% among those with severe frailty. CONCLUSION: frailty adversely impacts on patient-reported outcomes following hip and knee arthroplasty. However, even among those with severe frailty, the large majority achieved the MIC in OHS/OKS and reported a successful outcome.

The p38/HOG stress-activated protein kinase network couples growth to division in Candida albicans.

Cell size is a complex trait that responds to developmental and environmental cues. Quantitative size analysis of mutant strain collections disrupted for protein kinases and transcriptional regulators in the pathogenic yeast Candida albicans uncovered 66 genes that altered cell size, few of which overlapped with known size genes in the budding yeast Saccharomyces cerevisiae. A potent size regulator specific to C. albicans was the conserved p38/HOG MAPK module that mediates the osmostress response. Basal HOG activity inhibited the SBF G1/S transcription factor complex in a stress-independent fashion to delay the G1/S transition. The HOG network also governed ribosome biogenesis through the master transcriptional regulator Sfp1. Hog1 bound to the promoters and cognate transcription factors for ribosome biogenesis regulons and interacted genetically with the SBF G1/S machinery, and thereby directly linked cell growth and division. These results illuminate the evolutionary plasticity of size control and identify the HOG module as a nexus of cell cycle and growth regulation.

Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma.

BACKGROUND & AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored. METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits. RESULTS: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals. CONCLUSIONS: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.