Leisure-time and occupational physical activity and risk of cardiovascular disease incidence: a systematic-review and dose-response meta-analysis of prospective cohort studies.

BACKGROUND AND OBJECTIVE: Physical activity has benefits for the cardiovascular system, however, what levels and types of activity provide optimal cardiovascular health is unclear. We aimed to determine the level of physical activity that has the most benefits against cardiovascular diseases (CVD). METHODS: PubMed, Scopus, and Web of Science were searched for prospective cohort studies on leisure-time (LTPA) or occupational physical activity (OPA) as the exposure and major types of CVD (total CVD, coronary heart disease [CHD], stroke, and atrial fibrillation [AF]) incidence as the outcome. Risk of bias of studies was evaluated using the ROBINS-I tool. Summary hazard ratios (HR) were calculated using random-effects pairwise model. RESULTS: A total of 103 studies were included in the analysis. The highest versus the lowest LTPA was associated with a lower risk of overall CVD (HR = 0.81; 95% CI: 0.77-0.86), CHD (HR = 0.83; 0.79-0.88), and stroke (HR = 0.83; 0.79-0.88), but not AF (HR = 0.98; 0.92-1.05). Linear dose-response analyses showed a 10%, 12%, 9%, and 8% risk reduction in CVD, CHD, stroke, and AF incidence, respectively, for every 20 MET-hours/week increase in LTPA. In nonlinear dose-response analyses, there were inverse associations up to 20 MET-hours/week with 19% and 20% reduction in CVD and CHD risk, and up to 25 MET-hours/week with 22% reduction in stroke, with no further risk reduction at higher LTPA levels. For AF, there was a U-shaped nonlinear association with the maximum 8% risk reduction at 10 MET-hours/week of LTPA. Higher levels of OPA were not associated with risk of CVD, CHD, stroke, or AF. CONCLUSIONS: Overall, results showed an inverse dose-response relationship between LTPA and risk of CVD, CHD, stroke, and AF. Running was the most beneficial LTPA but the risk was similar among various LTPA intensities. OPA showed no benefits in total or any type of CVD.

Covariates of a healthy diet and physical activity self-management one year after Bariatric surgery: A cross-sectional study.

BACKGROUND: Healthy diet and physical activity self-management is important in maintaining weight loss and preventing weight regain after bariatric surgery. We aimed at evaluating covariates of healthy diet and physical activity self-management among patients undergone bariatric surgery using Health Action Process Approach (HAPA) model. METHOD: In this cross-sectional study, 272 patients with a history of bariatric surgery were selected from the data registry of Tehran Obesity Treatment Study (TOTS). Data were collected using bariatric surgery self-management standard questionnaire (BSSQ), and items based on HAPA model for healthy diet and physical activity self-management. Data were analyzed using Path analysis and AMOS version 24. RESULTS: The mean score of self-management was (32 ± 10SD). Coping planning construct (ß = 0.22; p<0.001) and risk perception (ß = 0.02; p<0.01) in dietary self-management and action planning (ß = 0.16; p = 0.001) and risk perception (ß = 0.001; p = 0.17) in physical activity self-management had the highest and lowest effect powers, respectively. Coping planning (ß = 0.22; p<0.001) and action planning (ß = 0.17; p<0.03) in diet, and action planning (ß = 0.16; p = 0.010) in physical activity were significantly related to self-management. Also, task-coping self-efficacy (ß = 0.28; and p<0.001), outcome expectancies (ß = 0.37; p<0.001), risk perception (ß = 0.13; p = 0.015) in diet and coping self-efficacy (ß = 0.50; p<0.001), outcome expectancies (ß = 0.12; p = 0.021) in physical activity were significantly related to behavioral intention. The values of CFI = 0.939 and RMSEA = 0.052 for diet and CFI = 0.948 and RMSEA = 0.048 for physical activity indicated adequate fit. CONCLUSION: HAPA was applicable as a framework for interventions promoting healthy diet and physical activity self-management in patients who have undergone bariatric surgery.

Enhancement of cisplatin-induced apoptosis by saffron in human lung cancer cells.

BACKGROUND: Cisplatin is a prevalent chemotherapeutic agent, and it has been used extensively to treat lung cancer. However, its clinical efficacy is hampered by its safety profile and dose-limiting toxicity. Saffron is a natural product that has shown significant anticancer effects. The combination treatment of saffron with chemotherapeutic agents has been considered a new strategy. METHODS: Herein, saffron extract as a natural anticancer substance was combined with cisplatin to assess their combined efficacy against tumor development in vitro. In A549 and QU-DB cell lines, the combined effect of the saffron extract with cisplatin led to a significant reduction in cell viability as compared to cisplatin alone. RESULTS: After 48 h incubation a considerable reduction in ROS levels in the QU-DB cell line upon treatment with cisplatin in the presence of saffron extract in comparison with cells treated with cisplatin alone. Furthermore, apoptosis increased significantly when in cells treated with cisplatin in combination with saffron extract compared to cisplatin alone. CONCLUSION: Our data establish that the combination of saffron extract as a natural anticancer substance with cisplatin leads to improved cell toxicity of cisplatin as an anticancer agent. Therefore, the saffron extract could be potentially used as an additive to enable a reduction in cisplatin dosages and its side effects.

The Effect of Family-Centered Intervention on Key Indicators of Diabetes Management and Control in Patients with Type-2 Diabetes.

Background: This study is to determine the effect of the family-centered intervention (FCIS) on the key indicators of diabetes management and Control control in patients with type-2 diabetes. Method: The present study is a quiz- experimental study with a randomized control group. Participants were 64 patients with type-2 diabetes visiting Ali Asghar Hospital of Isfahan in 2018. The eligible patients were assigned to either the intervention group or the control group (i.e., patient-center care) through block randomization. FCIS were implemented in 4 two-hour sessions as home visits while the patients and their caregivers were present. Data were collected twice-i.e. before the intervention and 12 weeks after it- and were analyzed, by running a t-test (α = 0.05), using SPSS-21. Results: The mean ± SD age of participants was 50.4 ± 8.5. There was no significant difference between the two groups in the mean weight, serum levels of FBS and A1C, physical activity, energy intake, and BMI before intervention. But, a significant improvement in the mean values of these variables in the intervention group after the intervention, compared with the control group was indicated (P < 0.05). Conclusions: This study suggests that FCIS are more effective than patient-center care in the management and control of type-2 diabetes. Therefore, it is recommended that the family be considered in educational interventions.

Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity.

The metabolic state represents a major hurdle for an effective adoptive T cell therapy (ACT). Indeed, specific lipids can harm CD8+ T cell (CTL) mitochondrial integrity, leading to defective antitumor responses. However, the extent to which lipids can affect the CTL functions and fate remains unexplored. Here, we show that linoleic acid (LA) is a major positive regulator of CTL activity by improving metabolic fitness, preventing exhaustion, and stimulating a memory-like phenotype with superior effector functions. We report that LA treatment enhances the formation of ER-mitochondria contacts (MERC), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a direct consequence, the antitumor potency of LA-instructed CD8 T cells is superior in vitro and in vivo. We thus propose LA treatment as an ACT potentiator in tumor therapy.

Dietary Advanced Glycation End Products and Risk of Overall and Cause-Specific Mortality: Results from the Golestan Cohort Study.

Controversy exists regarding the association of dietary advanced glycation end products (dAGEs) with the risk of disease outcomes and mortality. We aimed to examine, prospectively, the association between dAGEs intake and the risk of overall and cause-specific mortality in the Golestan Cohort Study. The cohort was conducted between 2004 and 2008 in Golestan Province (Iran) recruiting 50,045 participants aged 40-75 years. Assessment of dietary intake over the last year was performed at baseline using a 116-item food frequency questionnaire. The dAGEs values for each individual were calculated based on published databases of AGE values of various food items. The main outcome was overall mortality at the time of follow-up (13.5 years). Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and cause-specific mortality were estimated according to the dAGEs quintiles. During 656, 532 person-years of follow-up, 5406 deaths in men and 4722 deaths in women were reported. Participants at the highest quintile of dAGE had a lower risk of overall mortality (HR: 0.89, 95% CI: 0.84, 0.95), CVD mortality (HR: 0.89, 95% CI: 0.84, 0.95), and death from other causes (HR: 0.89, 95% CI: 0.84, 0.95) compared to those in the first quintile after adjusting for confounders. We found no association of dAGEs with risk of mortality from cancer (all), respiratory and infectious diseases, and injuries. Our findings do not confirm a positive association between dAGEs and the risk of mortality in Iranian adults. There is still no agreement among studies investigating dAGEs and their health-related aspects. So, further high-quality studies are required to clarify this association.

Maternal circulating leptin, tumor necrosis factor-alpha, and interleukine-6 in association with gestational diabetes mellitus: a systematic review and meta-analysis.

Background: Over the last decade, an emerging role of novel cytokines in the pathogenesis of gestational diabetes mellitus (GDM) has been proposed. The present study was implemented to provide a more accurate estimate of the effect size of the association between leptin, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) and the risk of GDM.Methods: Online databases were looked up to January 2023 using the search string: (leptin OR TNF-α OR IL-6) AND "gestational diabetes." Observational studies investigating the association of selected cytokines and GDM risk were included. Odds ratios and their 95% confidence intervals (CIs) were extracted and random-effects models were used to estimate the pooled effect.Results: Twenty-four studies were included in the meta-analysis. A significant association was found between higher circulating leptin and the risk of GDM and the pooled estimate was 1.16 (95%CI: 1.07, 1.27). Higher circulating levels of IL-6 and TNF-α were associated with increased risk of GDM, and the pooled estimates were 1.35 (95%CI: 1.05, 1.73) and 1.28 (95%CI: 1.01, 1.62), respectively.Conclusions: The studied cytokines could be implicated in the GDM pathogenesis and used as potential biomarkers for assessing the GDM risk. Additional longitudinal studies with large sample sizes are needed for a further evaluation of these findings.

The relationship between major food sources of fructose and cardiovascular disease, cancer, and all-cause mortality: a systematic review and dose-response meta-analysis of cohort studies.

We aimed to summarize the associations between food sources of fructose and cardiovascular diseases (CVD), cancer, and all-cause mortality risk using a systematic review and meta-analysis. We searched PubMed, Scopus, and Web of Science up to November 2020. We included cohort studies that investigated the relationship between mortality risk (all-cause, CVD, specific CVD, and total and site-specific cancers) and intake of ≥1 food source of fructose (fruit, fruit juice, breakfast cereals, sugar-sweetened beverages (SSBs), sweets, and yogurt) in general adult population. Summary hazard ratios and 95% CIs were estimated using a random-effects model for linear and nonlinear relationships. Findings indicated that each 100 g/d increase in fruit intake was associated with 8-13% lower risk of CVDs, stroke, gastrointestinal, and lung cancer mortality. For all-cause mortality, there was a beneficial relationship up to 200 g/d fruit, and then plateaued. For ischemic heart disease and cancer mortality, there was a beneficial relationship up to 300 g/d followed by a slight increase. Ingestion of breakfast cereals and sweets was also associated with lower risk of all-cause mortality. For yogurt, a non-linear marginal decrease in all-cause mortality was found. Ingestion of each 200 g/d yogurt was associated with a 14% lower risk of CVD mortality. Every 60 g/d increase in sweet intake was linked to a 5% lower risk of all-cause mortality. Contrariwise, every 250 g/d increase in SSBs intake was associated with 7-10% higher risk of all-cause and CVD mortality. In conclusion, beneficial associations were found between fruit, breakfast cereals, sweets, and yogurt with all-cause and/or CVD mortality risk. Fruit intake had also an inverse link with cancer mortality. Conversely, SSBs had a harmful relationship with all-cause and CVD mortality.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.2000361 .Registry number: CRD42019144956.

The effects of fasting diets on nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. There is no confirmed treatment for NAFLD as yet. Recently, fasting regimens and their relationship to NAFLD have drawn a great deal of attention in the literature. We review the current evidence that supports fasting diets as an adjunctive therapeutic strategy for patients with NAFLD and address potential action mechanisms. We reason that the fasting diets might be a promising approach for modulating hepatic steatosis, fibroblast growth factors 19 and 21 signaling, lipophagy, and the metabolic profile.

Fasting diets: what are the impacts on eating behaviors, sleep, mood, and well-being?

Fasting diets (FDs) have drawn great attention concerning their contribution to health and disease over the last decade. Despite considerable interest in FDs, the effect of fasting diets on eating behaviors, sleep, and mood-essential components of diet satisfaction and mental health- has not been addressed comprehensively. Understanding the critical role that fasting plays in these elements will open up potential treatment avenues that have not yet been explored. The aim of the present paper was to conduct a comprehensive critical review exploring the effects of fasting on eating behaviors, sleep, and mood. There is currently a lack of clarity regarding which fasting option yields the most advantageous effects, and there is also a scarcity of consistent trials that assess the effects of FDs in a comparable manner. Similarly, the effects and/or treatment options for utilizing FDs to modify eating and sleep behaviors and enhance mood are still poorly understood. Further researches aiming at understanding the impacts of various fasting regimes, providing new insights into the gut-brain axis and offering new treatment avenues for those with resistant anxiety and depression, are warranted. Alteration of eating behaviors can have lasting effects on various physiological parameters. The use of fasting cures can underpin ancient knowledge with scientific evidence to form a new approach to the prevention and treatment of problems associated with co-morbidities or challenges pertaining to eating behaviors. Therefore, a thorough examination of the various fasting regimens and how they impact disease patterns is also warranted.

The effect of vitamin D supplementation on oxidative stress and inflammatory biomarkers in pregnant women: a systematic review and meta-analysis of clinical trials.

BACKGROUND: Vitamin D deficiency, a common problem among pregnant women, is linked with maternal inflammation, oxidative stress and consequent adverse pregnancy outcomes. The aim of this systematic review was to evaluate the effect of vitamin D supplementation on oxidative stress and inflammatory biomarkers in pregnant women according to the PRISMA guidance. METHODS: Four databases including PubMed/MEDLINE, Scopus, Web of Science and Cochrane were used for searching papers published until 25th July 2022. Clinical trials that assessed 25-Hydroxyvitamin D (25(OH)D), inflammatory markers (including high sensitivity C-reactive protein (hs-CRP) and certain cytokines) and oxidative stress markers (including malondialdehyde (MDA), total antioxidant capacity (TAC) and glutathione (GSH)) in pregnant women, were included in this review. The primary search of three databases displayed 21571 records. After removing duplicates and irrelevant articles, 17 eligible RCTs included for more evaluation. Random effect model and Der Simonian-Laird method were used to pool the data of studies. Risk of bias assessed according to version 2 of the Cochrane risk-of-bias tool for randomized trials. RESULTS: According to the meta-analysis result, vitamin D supplementation caused a significant increase in the maternal circulating concentrations of 25(OH)D (SMD 2.07; 95%, CI 1.51, 2.63; p < 0.001), TAC (SMD 2.13, 95% CI 1.04 to 3.23, p < 0.001) and GSH (SMD 4.37, 95% CI 2.9 to 5.74, p < 0.001) as well as a significant decrease in the levels of MDA (SMD -0.46, 95% CI -0.87 to -0.05, p = 0.02). However, it had no significant impact on hs-CRP concentrations (SMD 0.24; 95% CI, -0.55, 1.03; p = 0.50). CONCLUSION: In the present study, vitamin D supplementation led to increased levels of 25(OH)D, TAC and GSH and also decreased concentration of MDA. Nevertheless, because of low certainty of evidence, these findings have to be declared conservatively. TRIAL REGISTRATION: Registration code in PROSPERO website: CRD42020202600.

Comparing the risk of cardiovascular diseases and all-cause mortality in four lifestyles with a combination of high/low physical activity and healthy/unhealthy diet: a prospective cohort study.

BACKGROUND: In this study, we assessed the risk of cardiovascular diseases (CVDs) and all-cause mortality in subjects having an only physical activity or a healthy diet or both compared to those having none of these healthy behaviors in the Golestan Cohort Study (GCS). METHODS: A total of 50,045 participants aged ≥ 40 years were recruited from Golestan Province, Iran, from 2004 to 2008 and followed for a median of 13.9 years. Four lifestyles were compared: healthy diet and active (HDA), healthy diet but inactive (HDI), unhealthy diet but active (UDA), and unhealthy diet and inactive (UDI), with UDI being considered as the reference group. Diet quality was assessed by the Dietary Approaches to Stop Hypertension diet score, which was calculated based on a validated food frequency questionnaire. The primary outcomes were death from any cause and CVDs. Adjusted Cox models were used to estimate the hazards ratio (HR) and 95% confidence intervals (CI) for overall and CVDs mortality. RESULTS: During 467,401 person-years of follow-up, 6,256 overall deaths and 2,043 confirmed CVDs deaths were reported. After adjustment for potential confounders, there was a significant lower risk for all-cause mortality in participants with both healthy behaviors (HR = 0.79, 95% CI = 0.73 to 0.86) or only one healthy behavior [HDI: HR = 0.84, 95% CI = 0.78 to 0.90)] and [UDI: HR = 0.91, 95% CI = 0.85 to 0.97] compared to those with both unhealthy behaviors. For CVDs mortality, the HDA lifestyle (HR = 0.74, 95%CI = 0.65 to 0.86), as well as the UDA lifestyle (HR = 0.83, 95%CI = 0.74 to 0.94) indicated a significant lower risk compared to the UDI lifestyle. The HDI lifestyle was not more effective than UDI. CONCLUSION: The greatest reduction in all-cause and CVDs mortality was related to the HDA. For all-cause mortality, both HDI and UDA lifestyles were associated with a decreased risk in comparison to UDI, but for CVDs mortality, only UDA but not HDI decreased the risk.

Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells.

Acute graft versus host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) inflicted by alloreactive T cells primed in secondary lymphoid organs (SLOs) and subsequent damage to aGvHD target tissues. In recent years, Treg transfer and/or expansion has emerged as a promising therapy to modulate aGvHD. However, cellular niches essential for fostering Tregs to prevent aGvHD have not been explored. Here, we tested whether and to what extent MHC class II (MHCII) expressed on Ccl19+ fibroblastic reticular cells (FRCs) shape the donor CD4+ T cell response during aGvHD. Animals lacking MHCII expression on Ccl19-Cre-expressing FRCs (MHCIIΔCcl19) showed aberrant CD4+ T cell activation in the effector phase, resulting in exacerbated aGvHD that was associated with significantly reduced expansion of Foxp3+ Tregs and invariant NK T (iNKT) cells. Skewed Treg maintenance in MHCIIΔCcl19 mice resulted in loss of protection from aGvHD provided by adoptively transferred donor Tregs. In contrast, although FRCs upregulated costimulatory surface receptors, and although they degraded and processed exogenous antigens after myeloablative irradiation, FRCs were dispensable to activate alloreactive CD4+ T cells in 2 mouse models of aGvHD. In summary, these data reveal an immunoprotective, MHCII-mediated function of FRC niches in secondary lymphoid organs (SLOs) after allo-HCT and highlight a framework of cellular and molecular interactions that regulate CD4+ T cell alloimmunity.

Recent advances in oral delivery of bioactive molecules: Focus on prebiotic carbohydrates as vehicle matrices.

Controlled oral delivery of bioactive molecules remains a promising platform for the food and biomedical realm. Nonetheless, there are many bottlenecks to the efficient oral bioactive delivery that necessitates the development of advanced approaches. In recent years, prebiotic carbohydrates have drawn surging interest for targeted bioactive delivery due to their potential of multi-stimuli release mechanisms. Harnessing prebiotic-based vehicles confers novel possibilities for intact oral bioactive delivery, improving their bioavailability and efficacy. This critical review updates state of the art on progresses in oral delivery of natural active agents via prebiotic carbohydrates. We offer the latest advances concerning prebiotic-based vehicles (i.e., pH/time-dependent systems, enzyme-sensitive polymers, and colonic microbiota-dependent vehicles), emphasizing their key attributes to attaining controlled/targeted bioactive delivery to the intended locus. Finally, we discuss safety considerations, challenges, and future perspectives toward advances in the field.

JMJD3 activated hyaluronan synthesis drives muscle regeneration in an inflammatory environment.

Muscle stem cells (MuSCs) reside in a specialized niche that ensures their regenerative capacity. Although we know that innate immune cells infiltrate the niche in response to injury, it remains unclear how MuSCs adapt to this altered environment for initiating repair. Here, we demonstrate that inflammatory cytokine signaling from the regenerative niche impairs the ability of quiescent MuSCs to reenter the cell cycle. The histone H3 lysine 27 (H3K27) demethylase JMJD3, but not UTX, allowed MuSCs to overcome inhibitory inflammation signaling by removing trimethylated H3K27 (H3K27me3) marks at the Has2 locus to initiate production of hyaluronic acid, which in turn established an extracellular matrix competent for integrating signals that direct MuSCs to exit quiescence. Thus, JMJD3-driven hyaluronic acid synthesis plays a proregenerative role that allows MuSC adaptation to inflammation and the initiation of muscle repair.

Severity of Disease and COVID-19 Complications During Hospital Stay: A Prospective Cohort Study.

BACKGROUND: COVID-19, with its high transmission and mortality rates and unknown outcomes, has become a major concern in the world. Among people with COVID-19, severe cases can quickly progress to serious complications, and even death. So, the present study aimed to examine the relationship between the severity of the disease and the outcome in patients afflicted by COVID-19 during hospitalization. METHODS: A total of 653 patients with COVID-19 aged 18 years or older were included from Khorshid hospital in Isfahan, Iran and followed for a mean of 22.72 days (median 23.50; range 1-47). Severe COVID-19 was defined by respiration rate≥30 times/min, oxygen saturation level≤88% in the resting position, and pulse rate≥130/min. The primary outcome was mortality. The secondary outcomes included need for mechanical ventilation and intensive care unit (ICU) admission. RESULTS: During 4233 person-days of follow-up, 49 (7.5%) deaths, 27 (4.1%) invasive ventilation and 89 (13.6%) ICU admissions in hospital were reported. After adjustment for potential confounders, severity of the disease was positively associated with risk of mortality, invasive ventilation and ICU admissions (hazard ratio [HR]: 5.99; 95% CI: 2.85, 12.59; P<0.001, HR: 7.09; 95% CI: 3.24, 15.52; P<0.001 and HR: 4.88; 95% CI: 2.98, 7.98; P<0.001, respectively). In addition, greater age (HR=1.04; 95% CI=1.02-1.07; P=0.002), chronic kidney disease (HR=3.05; 95% CI=1.35, 6.90; P=0.008), blood urea nitrogen (BUN) (HR=1.04; 95% CI=1.03-1.05; P<0.001) and creatinine (HR=1.44; 95% CI=1.26-1.65; P<0.001) were probably significant risk factors for mortality in severe COVID-19 patients. CONCLUSION: More intensive therapy and special monitoring should be implemented for patients with older age, hypertension and kidney disease who are infected with COVID-19 to prevent rapid worsening.

The Effect of Vitamin D Supplementation on Serum 25-Hydroxy Vitamin D in the Patients Undergoing Bariatric Surgery: a Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Currently, there is no consensus on the optimal vitamin D administration in bariatric patients. The present systematic review and meta-analysis were conducted to examine the effect of vitamin D supplements on serum level of 25(OH) vitamin D in the patients undergoing bariatric surgery (BS).Random model effects were used to estimate standardized mean difference (SMD) with a 95% confidence interval (CI). Nine clinical trials were included in the meta-analysis. Vitamin D supplementation in patients undergoing BS modestly improves vitamin D status (SMD, 0.53; 95% CI, 0.28, 0.77) particularly, in the dosages above 2850 IU/day and in the patients with BMI greater than 50 kg/m2. Vitamin D supplementation was associated with prevention of raising of the PTH serum concentration and without impact on serum calcium levels.

Junctional adhesion molecule C expression specifies a CD138low/neg multiple myeloma cell population in mice and humans.

Deregulation such as overexpression of adhesion molecules influences cancer progression and survival. Metastasis of malignant cells from their primary tumor site to distant organs is the most common reason for cancer-related deaths. Junctional adhesion molecule-C (JAM-C), a member of the immunoglobulin-like JAM family, can homodimerize and aid cancer cell migration and metastasis. Here we show that this molecule is dynamically expressed on multiple myeloma (MM) cells in the bone marrow and co-localizes with blood vessels within the bone marrow of patients and mice. In addition, upregulation of JAM-C inversely correlates with the downregulation of the canonical plasma cell marker CD138 (syndecan-1), whose surface expression has recently been found to dynamically regulate a switch between MM growth in situ and MM dissemination. Moreover, targeting JAM-C in a syngeneic in vivo MM model ameliorates MM progression and improves outcome. Overall, our data demonstrate that JAM-C might serve not only as an additional novel diagnostic biomarker but also as a therapeutic target in MM disease.

Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression.

Multiple myeloma remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow microenvironment harbors treatment-resistant myeloma cells, which eventually lead to disease relapse in patients. In the bone marrow, CD4+FoxP3+ regulatory T cells (Tregs) are highly abundant amongst CD4+ T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in multiple myeloma dissemination to bone marrow compartments and disease progression. To investigate the immune regulation of multiple myeloma, we utilized syngeneic immunocompetent murine multiple myeloma models in two different genetic backgrounds. Analyzing the spatial immune architecture of multiple myeloma revealed that the bone marrow Tregs accumulated in the vicinity of malignant plasma cells and displayed an activated phenotype. In vivo Treg depletion prevented multiple myeloma dissemination in both models. Importantly, short-term in vivo depletion of Tregs in mice with established multiple myeloma evoked a potent CD8 T cell- and NK cell-mediated immune response resulting in complete and stable remission. Conclusively, this preclinical in-vivo study suggests that Tregs are an attractive target for the treatment of multiple myeloma.

Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia.

Ribosome dysfunction underlies the pathogenesis of many cancers and heritable ribosomopathies. Here, we investigate how mutations in either ribosomal protein large (RPL) or ribosomal protein small (RPS) subunit genes selectively affect erythroid progenitor development and clinical phenotypes in Diamond-Blackfan anemia (DBA), a rare ribosomopathy with limited therapeutic options. Using single-cell assays of patient-derived bone marrow, we delineated two distinct cellular trajectories segregating with ribosomal protein genotypes. Almost complete loss of erythroid specification was observed in RPS-DBA. In contrast, we observed relative preservation of qualitatively abnormal erythroid progenitors and precursors in RPL-DBA. Although both DBA genotypes exhibited a proinflammatory bone marrow milieu, RPS-DBA was characterized by erythroid differentiation arrest, whereas RPL-DBA was characterized by preserved GATA1 expression and activity. Compensatory stress erythropoiesis in RPL-DBA exhibited disordered differentiation underpinned by an altered glucocorticoid molecular signature, including reduced ZFP36L2 expression, leading to milder anemia and improved corticosteroid response. This integrative analysis approach identified distinct pathways of erythroid failure and defined genotype-phenotype correlations in DBA. These findings may help facilitate therapeutic target discovery.