Low Response Research Articles

Functional heterogeneity of cancer-associated fibroblasts with distinct neoadjuvant immunotherapy plus chemotherapy response in esophageal squamous cell carcinoma

Novel neoadjuvant immunotherapy combined with chemotherapy (neoICT) has improved outcomes for patients with esophageal squamous-cell carcinoma (ESCC), but challenges persist in low response rates and therapy resistance. Little is known about the intra-tumoral heterogeneity in the ESCC tumor microenvironment (TME) that underlies differential responses to neoadjuvant therapy. We applied single-cell RNA sequencing (scRNA-seq) profiling and multiplexed immunofluorescence staining to thoroughly decipher the TME in ESCC specimens from a neoadjuvant anti-PD1 combination therapy clinical trial. The cancer-associated fibroblasts (CAFs) population showed the significant alteration in abundance following neoadjuvant therapy. Specifically, IL6 + CCL2 + immunomodulatory CAFs and a novel CD248 + mechanoresponsive CAFs subset exhibited increasing infiltration. Mechanistically, CD248 + mechanoresponsive CAFs approached and lined the tumor nest to physically block the infiltration of CD8 + T cells and drug delivery, while IL6 + CCL2 + immunomodulatory CAFs induced therapeutic resistance with distinct IL-6 expression. Among patients treated with neoICT, we observed prominent CAF-T cell interactions. In particular, the NECTIN2-TIGIT ligand-receptor pair was enriched in treated samples, and TIGIT was identified as the major inhibitory checkpoint of T cells. Our findings demonstrate distinct alterations in TME constituent responses to neoadjuvant immunotherapy and identify functional phenotypes of CAFs associated with unfavorable therapeutic responses in patients. This provides potential targets to enhance responses to neoadjuvant therapy in ESCC.

Anekomochi glutinous rice provides low postprandial glycemic response by enhanced insulin action via GLP-1 release and vagal afferents activation

Glutinous rice (mochi rice), compared to non-glutinous rice (uruchi rice), exhibits a wide range of glycemic index (GI) values, from low to high. However, the underlying mechanisms behind the variation in GI values remain poorly understood. In this study, we aimed to identify rice cultivars with a low postprandial glycemic response and investigate the mechanisms, focusing on insulin and incretin hormones. We examined seven glutinous rice cultivars and three non-glutinous rice cultivars. We discovered that Anekomochi, a glutinous rice cultivar, has the lowest postprandial glycemic response. Anekomochi significantly enhanced glucagon-like peptide-1 (GLP-1) secretion while suppressing insulin secretion. These effects were completely blunted by inhibiting GLP-1 receptor signaling and denervating the common hepatic branch of vagal afferent nerves that are crucial for sensing intestinal GLP-1. Our findings demonstrate that Anekomochi markedly enhances insulin action via GLP-1 release and vagal afferent neural pathways, thereby leading to a lower postprandial glycemic response.

Application of placing the anterior end of endotracheal tube at the glottis in laryngeal mask airway positive ventilation during general anesthesia: A prospective, randomized, controlled trial.

Glottic contraction and closure causes ventilation obstruction and laryngeal mask airway (LMA) leakage during positive pressure ventilation using LMA. This study aimed to assess the effect of placing the anterior end of the endotracheal tube (ET) at the glottis through the LMA ventilation conduit on treating LMA leakage following glottic contraction and closure. In this prospective, randomized, controlled trial, patients with non-minor surgery using LMA ventilation were randomly allocated to the i-gel group (group L) and the i-gel combined with ET group (group LE). The tip of ET was placed 2 cm under glottis guided by fiberoptic bronchoscope through i-gel ventilation conduit in group LE. The perioperative incidence of i-gel leakage, the changes of systolic blood pressure (SBP) and heart rate (HR) following artificial airway insertion, and adverse events were recorded. Perioperative i-gel leakage was observed in 7 of 48 patients (14.6%) in group L and 1 of 49 patients (2.0%) in group LE. There was significant difference in the incidence of leakage between the 2 groups (P = .031). SBP and HR after ET insertion in group LE increased significantly compared to those in group L (P < .05/5). The values of both SBP and HR after ET insertion did not exceed the basic values in group LE (P > .05/4). There were no significant differences in the incidence and severity of postoperative sore pain and hoarseness, cough during i-gel and ET removal between the 2 groups (P > .05). Placing the anterior end of ET at the glottis reduced LMA air leakage related to glottic contraction and closure in non-minor surgery. The ET placing had low stress response and did not significantly increase postoperative complications.

Decoding the impact of neighboring amino acids on ESI-MS intensity output through deep learning

Peptide-level quantification using mass spectrometry (MS) is no trivial task as the physicochemical properties affect both response and detectability. The specific amino acid (AA) sequence affects these properties, however the connection between sequence and intensity output remains poorly understood. In this work, we explore combinations of amino acid pairs (i.e., dimer motifs) to determine a potential relationship between the local amino acid environment and MS1 intensity. For this purpose, a deep learning (DL) model, consisting of an encoder-decoder with an attention mechanism, was built. The attention mechanism allowed to identify the most relevant motifs. Specific patterns were consistently observed where a bulky/aromatic and hydrophobic AA followed by a cationic AA as well as consecutive bulky/aromatic and hydrophobic AAs were found important for the prediction of the MS1 intensity. Correlating attention weights to mean MS1 intensities revealed that some important motifs, particularly containing Trp, His, and Cys, were linked with low responding peptides whereas motifs containing Lys and most bulky hydrophobic AAs were often associated with high responding peptides. Moreover, Asn-Gly was associated with low response. The model predicts MS1 response with a mean average percentage error of ∼11 % and a Pearson correlation coefficient of ∼0.64. While dimer representation of peptide sequences did not improve predictive capacity compared to single AA representation in earlier work, this work adds valuable insight for a better understanding of peptide response in MS analysis. SignificanceMass spectrometry is not inherently quantitative, and the response of a compound relies not only on its concentration but also on the molecular composition. For mass spectrometry-based analysis of peptides, such as in bottom-up proteomics, this directly implies that the response cannot be used directly to quantify individual peptides. Moreover, the dependency of the response on the amino acid sequence of individual peptides remains poorly understood. Using a deep learning model based on a recurrent neural network with an attention mechanism, we here investigate how the presence of dimer motifs within a peptide affects the MS1 response through the analysis of intended equimolar peptide pools comprising almost 200,000 unique peptides in total. Not only do we identify certain dimer classes and specific dimers that substantially affect the MS1 response, but the model is also able to predict peptide intensity with low error rates within the independent test subset. The findings not only improve our understanding of the link between sequence and response for peptides but also highlight the potential of utilizing deep learning for developing methods allowing for absolute, label-free peptide quantification.

T Cell Peptide Prediction, Immune Response, and Host–Pathogen Relationship in Vaccinated and Recovered from Mild COVID-19 Subjects

COVID-19 remains a significant threat, particularly to vulnerable populations. The emergence of new variants necessitates the development of treatments and vaccines that induce both humoral and cellular immunity. This study aimed to identify potentially immunogenic SARS-CoV-2 peptides and to explore the intricate host–pathogen interactions involving peripheral immune responses, memory profiles, and various demographic, clinical, and lifestyle factors. Using in silico and experimental methods, we identified several CD8-restricted SARS-CoV-2 peptides that are either poorly studied or have previously unreported immunogenicity: fifteen from the Spike and three each from non-structural proteins Nsp1-2-3-16. A Spike peptide, LA-9, demonstrated a 57% response rate in ELISpot assays using PBMCs from 14 HLA-A*02:01 positive, vaccinated, and mild-COVID-19 recovered subjects, indicating its potential for diagnostics, research, and multi-epitope vaccine platforms. We also found that younger individuals, with fewer vaccine doses and longer intervals since infection, showed lower anti-Spike (ELISA) and anti-Wuhan neutralizing antibodies (pseudovirus assay), higher naïve T cells, and lower central memory, effector memory, and CD4hiCD8low T cells (flow cytometry) compared to older subjects. In our cohort, a higher prevalence of Vδ2-γδ and DN T cells, and fewer naïve CD8 T cells, seemed to correlate with strong cellular and lower anti-NP antibody responses and to associate with Omicron infection, absence of confusional state, and habitual sporting activity.

Surveys With a Low Response Rate Are Unreliable for Estimating Prevalence.

Surveys With a Low Response Rate Are Unreliable for Estimating Prevalence.

Three doses of Sars-CoV-2 mRNA vaccine in older adults result in similar antibody responses but reduced cellular cytokine responses relative to younger adults

ObjectivesBooster COVID-19 vaccinations are used to protect the elderly, a group vulnerable to severe disease. We compared humoral and cellular immunity in older versus younger adults up to eight months after administering a BNT16b2 booster vaccine dose. Next, we analyzed the plasma levels of soluble T cell activation/exhaustion markers. MethodsHome-dwelling older adults (n = 68, median age 86) and younger healthcare workers (n = 35, median age 39), previously vaccinated with two doses of BNT162b2, were given a booster dose at ten months after the initial dose. Our analysis consisted of spike-specific IgG, neutralizing antibodies, memory B cells, IFN-γ and IL-2 secreting T cells and soluble T cell exhaustion/activation markers. ResultsFollowing the initial two doses, the elderly cohort exhibited lower humoral and IFN-γ responses compared to younger adults. The booster dose increased the humoral responses in both older and younger adults. At two months after the booster dose, older and younger vaccinees had comparable levels of antibodies and the responses were maintained up to 18 months. The younger cohort elicited an increase in the cellular response, while no increase was detected in the elderly. The elderly had higher plasma levels of soluble forms of the T cell activation/exhaustion markers CD25 and TIM-3, which inversely correlated with age and T-cell cytokine responses. This suggests that these markers may be related to the observed dysfunctional cellular cytokine response in older adults. However, both elderly and younger adults who experienced breakthrough infections after booster vaccination, elicited more robust humoral and IFN-γ responses. ConclusionsThe booster dose elicited neutralizing and spike-specific antibody responses in the elderly that were comparable with that of the younger cohort. However, the lack of a strong cellular cytokine response to the third dose in the elderly may explain their vulnerability to severe infection and may be a consequence of exhausted or senescent T cell responses. (https://clinicaltrials.gov/study/NCT04706390).

Women's experience of the information provided along with invitation to participate in BreastScreen Norway.

To explore how women aged 50-69 invited to BreastScreen Norway perceived the information provided along with the invitation letter, as well as time spent on reading this information. An anonymous questionnaire was sent, as a paper-based form along with a physical invitation letter, or as a link to a digital form in a digital invitation letter, to 84,543 women invited to BreastScreen Norway in 2022. The paper-based forms were handed in upon screening attendance. The women were invited to screening by physical or digital invitation including an information leaflet describing benefits and harms, or a link to similar information on a webpage. The questionnaire assessed women's perception of the information and time spent on reading it. Responses were presented by screening invitation type (physical/digital). A total of 9.9% (8355/84,543) of the women responded to the questionnaire. Among women invited by a physical letter, information about the screening examination and about benefits and harms was considered sufficient by 90% (4338/4797) and 89% (4246/4790), respectively, and 92% (4246/4790) reported the information to be sufficient to make an informed decision on participation. Among those invited digitally, the percentages were 83% (2788/3379), 78% (2618/3369), and 88% (2962/3370), respectively. About 59% (4807/8169) spent <5 min reading the information. Most of the respondents perceived the information received upon invitation to BreastScreen Norway sufficient to make an informed decision on participation and used <5 min to read the information. The results should be interpreted with caution due to the low response rate.

Nudging towards sustainability: Exploring the role of behavioral interventions in circular bio‐economy development for the fashion industry

AbstractThe fashion and food industries are major contributors to waste generation, making sustainability management a priority for both practitioners and scholars. This study examines how nudging can promote the development of a circular bioeconomy within the fashion industry, specifically investigating whether nudging techniques can facilitate the market adoption of fashion products made from sustainable textiles derived from food waste. Using a dataset of 2112 participants from four European countries, we employ regression and clustering analyses to identify consumer profiles based on psychological and behavioral characteristics. Our econometric analysis reveals that gender, education, and psychological factors such as environmental responsibility and awareness significantly impact sustainable behaviors. Additionally, a left‐leaning political orientation is positively associated with engagement in sustainable practices and willingness to pay for eco‐friendly products. Clustering analysis identifies distinct consumer profiles: “enthusiastic” individuals demonstrate high commitment to sustainability, while “skeptics” shows low engagement and responsiveness to environmental issues. The study offers key policy implications on the effectiveness of nudging interventions in enhancing the sustainability of the fashion industry.

An Ultrasensitive Bi2O2Se/In2S3 Photodetector with Low Detection Limit and Fast Response toward High-Precision Unmanned Driving.

The machine vision utilized in unmanned driving systems must possess the ability to accurately perceive scenes under low-light illumination conditions. To achieve this, photodetectors with low detection limits and a fast response are essential. Current systems rely on avalanche diodes or lidars, which come with the drawbacks of increased energy consumption and complexity. Here, we present an ultrasensitive photodetector based on a two-dimensional (2D) Bi2O2Se/In2S3 heterostructure, incorporating a homotype unilateral depletion band design. This innovative architecture effectively modulates the transport of both free and photoexcited carriers, suppressing the dark current and facilitating the rapid and efficient separation of photocarriers. Owing to these features, this device exhibits a responsivity of 144 A/W, a specific detectivity of 1.2 × 1014 Jones, and a light on/off ratio of 1.1 × 105. These metrics rank among the top values reported for state-of-the-art 2D devices. Moreover, this device also demonstrates a fast response time of 170/296 μs and a low noise equivalent power of 0.57 fW/Hz1/2, attributes that endow it with ultraweak light imaging capabilities. Furthermore, we have successfully integrated this device into an unmanned driving system, providing a perspective on the design and fabrication of future optoelectronic devices.

Bats generate lower affinity but higher diversity antibody responses than those of mice, but pathogen-binding capacity increases if protein is restricted in their diet.

Bats are reservoirs of many zoonotic viruses that are fatal in humans but do not cause disease in bats. Moreover, bats generate low neutralizing antibody titers in response to experimental viral infection, although more robust antibody responses have been observed in wild-caught bats during times of food stress. Here, we compared the antibody titers and B cell receptor (BCR) diversity of Jamaican fruit bats (Artibeus jamaicensis; JFBs) and BALB/c mice generated in response to T-dependent and T-independent antigens. We then manipulated the diet of JFBs and challenged them with H18N11 influenza A-like virus or a replication incompetent Nipah virus VSV (Nipah-riVSV). Under standard housing conditions, JFBs generated a lower avidity antibody response and possessed more BCR mRNA diversity compared to BALB/c mice. However, withholding protein from JFBs improved serum neutralization in response to Nipah-riVSV and improved serum antibody titers specific to H18 but reduced BCR mRNA diversity.

Targeting CD47 and Angiogenesis Demonstrates Effective Anti-Tumor Effect in Bladder Cancer.

Background: Although immunotherapy has shown potential in cancer treatment, current immunotherapeutics for bladder cancer are limited by a low response rate. Therefore, it is necessary to investigate other suitable immunotherapeutic targets and strategies for bladder cancer. Methods: To evaluate whether CD47 could be a suitable target for bladder cancer immunotherapy, CD47 protein expression levels in 116 bladder cancer tissue samples were assessed by IHC staining. In vitro anti-tumor effect of blocking CD47 was examined by phagocytosis assays. In vivo anti-tumor effects of targeting CD47 and angiogenesis were experimented in the HSPCs-CDX model. Results: We find that CD47 is highly expressed in bladder cancer samples and is associated with poor prognosis. Blocking CD47 could enhance the human PBMC-derived macrophages' phagocytosis of T24 (from 10.40% to 29.70%) and 5637 (from 5.31% to 33.52%) human bladder cancer cells, as well as demonstrate anti-tumor effects in the HSPCs-CDX model (tumor growth inhibition rate, TGI: 33.05%). During CD47 treatment, we observed that the level of angiogenesis increased after CD47 blockade, and it might undermine the effect of CD47 immunotherapy. We then combined CD47 blockade with anti-angiogenic drugs to treat bladder cancer and discovered that inhibiting angiogenesis could further improve the anti-tumor effect of CD47 blockade (TGI: 76.39%). Finally, we tested the anti-tumor effect of co-targeting CD47 and angiogenesis using a bispecific fusion protein, SIRPα-VEGFR1, which successfully inhibited tumor growth to a similar extent as a combination therapy. Conclusions: Our study suggests that targeting CD47 could inhibit the growth of bladder cancer by promoting macrophage-mediated anti-tumor immunity. Moreover, blocking CD47 and angiogenesis could achieve a potent anti-tumor effect and could be an effective immunotherapy strategy for bladder cancer.

Health outcomes of former division I college athletes

ABSTRACT Background Former professional collision sport (CS) athletes, particularly American football players, are at risk of developing chronic health conditions; however, little is known about the health outcomes of amateur athletes. Methods A 60-item health survey examined self-reported symptoms and diagnoses among former Division 1 Collegiate CS athletes and non- or limited-contact sport (non-CS) athletes. Binary logistic regressions tested the association between playing CS and health outcomes. Results Five hundred and two (6.2%) participants completed the survey: 160 CS athletes (mean age: 59.2, SD = 16.0) and 303 non-CS athletes (mean age: 54.0, SD = 16.9). CS athletes had increased odds of reported cognitive complaints and neuropsychiatric symptoms including memory (Padj < 0.01), attention/concentration (Padj = 0.01), problem solving/multi-tasking (Padj = 0.05), language (Padj = 0.02), anxiety (Padj = 0.04), impulsivity (Padj = 0.02), short-fuse/rage/explosivity (Padj < 0.001), and violence/aggression (Padj = 0.02). CS athletes also reported higher rates of sleep apnea (Padj = 0.02). There were no group differences in cardiovascular and physical health outcomes. Conclusions Former CS athletes reported more cognitive and neuropsychiatric complaints. The low response rate is a limitation of this study; however, over 500,000 athletes play college sports each year, thus research on long-term health outcomes in this population is critical.

Effect of Seed Treatment of Boron, Cobalt and Molybdenum on Growth Parameter, Grain Yield and Seed Quality in Soybean (Glycine max L.)

This study aimed to evaluate the effect of seed treatment of boron, cobalt and molybdenum on growth parameter, grain yield and seed quality in soybean (Glycine max L.) during kharif, during July, 2022 at experimental farm, department of Soil Science and Agricultural chemistry, College of Agriculture, Badnapur. The experiment was laid out in Randomized Block Design (RBD) with 8 treatments which were replicated thrice.The treatments comprises (T1) Absolute control, (T2) RDF, (T3) RDF + Boron @ 2 gm kg-1 seed, (T4) RDF + Cobalt @ 1.5 gm kg-1 seed, (T5) RDF + Ammonium molybdate 1 gm kg-1 seed , (T6) RDF + Boron @ 2 gm kg-1 seed + Cobalt @ 1.5 gm kg-1 seed, (T7) RDF + Cobalt @ 1.5 gm kg-1 seed + Ammonium molybdate @ 1 gm kg-1 seed, (T8) RDF + Boron @ 2 gm kg-1 seed + Cobalt @ 1.5 gm kg-1 + Ammonium molybdate @ 1 gm kg-1 seed .To achieve the objectives the observations were recorded at various growth stages of soybean kharif, during 2022. The result indicates that, treatment (T8) receiving RDF + Boron @ 2 gm kg-1 seed + Cobalt @ 1.5 gm kg-1 seed + Ammonium molybdate @ 1 gm kg-1seed was found effective due to advantages effect on morpho-physiological growth, yield and yield attributing characters likeplant height, nodulation, fresh weight of nodules, no. of root nodules, root length, number of pods plant-1of soybean grain yield, Stover yield of soybean. In grain quality the results revealed that test weight, protein content percentage were significantly influenced with the application of treatment T8. On the other hand, in all the cases the lower response was found from the control treatment.

Study of the effects of shallow-buried charge parameters on the lower limb injuries of occupant in special vehicle body

In the process of military missions, special vehicles often encounter shallow buried charge threats that will greatly affect the safety of the occupants. To study the integrated effects of shallow buried charge detonation point, height-to-diameter ratio, burial inclination, weight, and other key parameters on the lower limb injuries of occupant, this study was based on the special body of a shallow buried explosive test and numerical calculation methods. The reliability of the numerical model and the load effect mechanism of the shallow burial charge were studied. Based on this, the lower limb injuries response law of occupant was analyzed with respect to each parameter. The results showed that the bottom charge load mainly came from two-stage ejection loading, in which the first stage was a strong load with short-duration local impact loading and the second stage was a weak load with long-duration extended range loading. By comparing the lower limb injury response of occupant under different charge parameters, we found that the weight of charge had the greatest effect on the extent of occupant injury, followed by the height-to-diameter ratio and burial inclination, while the detonation position had a relatively small effect on the injury magnitude. Finally, a comprehensive prediction model of the lower limb injuries of occupant was obtained by using the Latin hypercube sampling method and the least-squares method, and it was verified that the model had a good matching accuracy.

OXGR1-Dependent (Pro)Renin Receptor Upregulation in Collecting Ducts of the Clipped Kidney Contributes to Na+ Balance in Goldblatt Hypertensive Mice.

The two-kidney, one-clip (2K1C) Goldblatt rodent model elicits a reduction in renal blood flow (RBF) in the clipped kidney (CK). The reduced RBF and oxygen bio-ability causes the accumulation of the tricarboxylic cycle intermediary, α-ketoglutarate, which activates the oxoglutarate receptor-1 (OXGR1). In the kidney, OXGR1 is abundantly expressed in intercalated cells (ICs) of the collecting duct (CD), thus contributing to sodium transport and electrolyte balance. The (pro)renin receptor (PRR), a member of the renin-angiotensin system (RAS), is a key regulator of sodium reabsorption and blood pressure (BP) that is expressed in ICs. The PRR is upregulated in 2K1C rats. Here, we tested the hypothesis that chronic reduction in RBF in the CK leads to OXGR1-dependent PRR upregulation in the CD and alters sodium balance and BP in 2K1C mice. To determine the role of OXGR1 in regulating the PRR in the CDs during renovascular hypertension, we performed 2K1C Goldblatt surgery (clip = 0.13 mm internal gap, 14 days) in two groups of male mice: (1) mice treated with Montelukast (OXGR1 antagonist; 5 mg/Kg/day); (2) OXGR1-/- knockout mice. Wild-type and sham-operated mice were used as controls. After 14 days, 2K1C mice showed increased systolic BP (SBP) (108 ± 11 vs. control 82 ± 5 mmHg, p < 0.01) and a lower natriuretic response after the saline challenge test. The CK group showed upregulation of erythropoietin, augmented α-ketoglutarate, and increased PRR expression in the renal medulla. The CK of OXGR1 knockout mice and mice subjected to the OXGR1 antagonist elicited impaired PRR upregulation, attenuated SBP, and better natriuretic responses. In 2K1C mice, the effect of reduced RBF on the OXGR1-dependent PRR upregulation in the CK may contribute to the anti-natriuretic and increased SBP responses.

Pain Is Modulated Differently Between Females with and without Patellofemoral Pain: Factors Related to Sensitization.

Patellofemoral pain (PFP) has poor long-term recovery outcomes. Central sensitization describes central nervous system changes altering pain modulation, which can complicate recovery (poorer prognosis, worse function). Signs of central sensitization include amplified pain facilitation, pain hypersensitivity, and impaired pain inhibition, which can be measured with temporal summation of pain (TSP), pressure pain thresholds (PPTs) and conditioned pain modulation (CPM), respectively. Sex differences exist for these test responses, but female-only PFP investigations of sensitization are uncommon. Understanding pain modulation in females with PFP could improve treatment protocols. To determine whether females with PFP exhibit signs of central sensitization (greater TSP, lower PPTs, reduced CPM) compared to pain-free females. Cross-sectional Setting: Laboratory Patients or Other Participants: Thirty-three females [(20 PFP, 13 pain-free); Age: PFP 29.2 ± 7 years, pain-free 28 ± 7 years; Height: PFP 166.7 ± 5.9cm, pain-free 166 ± 9.5cm, Mass: PFP 66.7 ± 9.6kg, pain-free 69.3 ± 7.5kg). TSP was assessed with ten punctate stimuli applied to the knee and calculated by the difference in pain intensity between beginning and end responses. PPTs were tested at four sites [3 for local hypersensitivity (knee), 1 for widespread hypersensitivity (hand)]. CPM was conducted by comparing PPTs during two conditions (baseline, ice immersion). CPM response was defined as the percent difference between conditions. Between-group differences in TSP response were analyzed with a Welch's test. Separate Welch's tests analyzed group comparisons of PPTs and CPM responses at four sites. Females with PFP exhibited greater TSP response (P=0.019) and lower CPM response at patella center (P=0.010) and hand sites (P=0.007) than pain-free females. PPT group differences were not observed at any site (P>0.0125). Females with PFP modulate pain differently than pain-free females. Clinicians should recognize signs of central sensitization and their potential impact on treatment options.

Immune-modulative nano-gel-nano system for patient-favorable cancer therapy

Current cancer immunotherapies exhibit low response rates attributed to suppressive tumor immune microenvironments (TIMEs). To address these unfavorable TIMEs, supplementation with tumor-associated antigens and stimulation of immune cells at target sites are indispensable for eliciting anti-tumoral immune responses. Previous research has explored the induction of immunotherapy through multiple injections and implants; however, these approaches lack consideration for patient convenience and the implementation of finely tunable immune response control systems to mitigate the side effects of over-inflammatory responses, such as cytokine storms. In this context, we describe a patient-centric nano-gel-nano system capable of sustained generation of tumor-associated antigens and release of adjuvants. This is achieved through the specific delivery of drugs to cancer cells and antigens/adjuvants to immune cells over the long term, maintaining proper concentrations within the tumor site with a single injection. This system demonstrates local immunity against tumors with a single injection, enhances the therapeutic efficacy of immune checkpoint blockades, and induces systemic and memory T cell responses, thus minimizing systemic side effects.

Biomarker Changes in Response to Tofacitinib Treatment in Patients with Polyarticular Course Juvenile Idiopathic Arthritis.

Examine levels of candidate blood-based biomarkers (CBB) in juvenile idiopathic arthritis (JIA) treated with tofacitinib. JIA patients who participated in clinical trial NCT02592434 received tofacitinib from baseline to week 18. Serial serum samples were assayed for CBB (S100A8/9, S100A12, IL-18, SAA, resistin, VEGF, Angiopoietin-1, Angiopoietin-2, MMP8, MMP2, TIMP1, Leptin, CXCL9, sIL2R, ICAM-1, sTNFr, IL-6, IL-23, MCP1, CCL18, and CCL20). Association of CBB with JIA response to treatment from baseline to week 18 were assessed. This study included 166 patients with polyarticular-course JIA. Paired serum samples from 143 patients were available at both baseline and week 18. There were 35% (50/143) of patients with a JIA-American College of Rheumatology 90 (JIA-ACR90) level improvement while 90/121/137 (63%/85%/96%) achieved JIA-ACR70/50/30 improvement at wk18. Despite small numerical differences by JIA category, there were no baseline CBB values that independently predicted a decrease in JADAS-27 or JIA-ACR90 response by week 18. Decrease in resistin level (baseline to week 18) was significantly associated with wk18 improvement in JADAS-27 and JIA-ACR90 response, after adjusting for age, sex, JIA disease duration and baseline resistin [(r2 0.79, SE, 0.070, p<0.01 and OR(95%CI) = 1.134(1.018,1.264)]. HLA-B27 positivity was significantly associated with not achieving a JIA-ACR90 response at week 18 (p=0.0097). Among the CBB included, only resistin was significantly associated with treatment response, and no CBB was identified that forecasts JIA improvement after initiation of tofacitinib. The association of HLA-B27 positivity with lower response to tofacitinib in JIA is intriguing and merits further study.

COVID-19 vaccination in people living with HIV: current data and perspectives.

There is no correlation between HIV per se and other risk factors for severe COVID-19 disease. Pivotal studies have shown that vaccination is one of the effective ways to prevent severe COVID-19 illness in the general population. Studies on people living with HIV (PLWH) are scarce. The majority of these studies with mRNA (BNT126b2 and mRNA-1273) and adenovirus vector (Ad26.COV2.2 and ChAdOx1) vaccines with a low number of patients included shows that PLWH on antiretroviral treatment and with CD4 count > 200/mm³ has a robust immune response. These vaccines are thus effective in preventing severe infection caused by severe acute respiratory syndrome coronavirus 2 in PLWH. However, PLWH with a CD4 count of < 200/mm³ and uncontrolled viral load (VL) seems to have a lower immune response. COVID-19 vaccines are safe in PLWH; adverse effects are mild or moderate, and their incidence is similar to non-HIV people (NHP). The CD4 count decreased significantly and transiently, and the VL rebounded insignificantly in a few patients. A complete vaccination including a third dose is, therefore, recommended. A booster dose with an mRNA vaccine is recommended in PLWH with an advanced stage of their disease.