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Prostate cancer is one of the few malignancies that includes vaccination as a treatment modality. Elements of an effective cancer vaccine should include the ability to elicit a Type I T-cell response and target multiple antigenic proteins expressed early in the disease. Using existing gene datasets encompassing normal prostate tissue and tumors with Gleason Score ≤ 6 and ≥ 8, 10 genes were identified that were upregulated and conserved in prostate cancer regardless of the aggressiveness of disease. These genes encoded proteins also expressed in prostatic intraepithelial neoplasia. Putative Class II epitopes derived from these proteins were predicted by a combination of algorithms and, using human peripheral blood, epitopes which selectively elicited IFN-γ or IL-10 dominant antigen specific cytokine secretion were determined. Th1 selective epitopes were identified for eight antigens. Epitopes from three antigens elicited Th1 dominant immunity in mice; PSMA, HPN, and AMACR. Each single antigen vaccine demonstrated significant anti-tumor activity inhibiting growth of implanted Myc-Cap cells after immunization as compared to control. Immunization with the combination of antigens, however, was superior to each alone in controlling tumor growth. When vaccination occurred simultaneously to tumor implant, multiantigen immunized mice had significantly smaller tumors than controls (p = 0.002) and a significantly improved overall survival (p = 0.0006). This multiantigen vaccine shows anti-tumor activity in a murine model of prostate cancer.

Prostate cancer is refractory to anti-CTLA-4 therapy, but the reason why is unclear. Padmanee Sharma and colleagues report that the inhibitory molecule VISTA, which negatively regulates T cells, is upregulated on macrophages in prostate tumors that have been treated with anti-CTLA-4 and may play a role in resistance to this immunotherapy. To date, anti-CTLA-4 (ipilimumab) or anti-PD-1 (nivolumab) monotherapy has not been demonstrated to be of substantial clinical benefit in patients with prostate cancer. To identify additional immune-inhibitory pathways in the prostate-tumor microenvironment, we evaluated untreated and ipilimumab-treated tumors from patients in a presurgical clinical trial. Levels of the PD-L1 and VISTA inhibitory molecules increased on independent subsets of macrophages in treated tumors. Our data suggest that VISTA represents another compensatory inhibitory pathway in prostate tumors after ipilimumab therapy.

Agriculture 4.0 is transforming farming livelihoods thanks to the development and adoption of technologies such as artificial intelligence, the Internet of Things and robotics, traditionally used in other productive sectors. Soft robotics and soft grippers in particular are promising approaches to lead to new solutions in this field due to the need to meet hygiene and manipulation requirements in unstructured environments and in operation with delicate products. This review aims to provide an in-depth look at soft end-effectors for agricultural applications, with a special emphasis on robotic harvesting. To that end, the current state of automatic picking tasks for several crops is analysed, identifying which of them lack automatic solutions, and which methods are commonly used based on the botanical characteristics of the fruits. The latest advances in the design and implementation of soft grippers are also presented and discussed, studying the properties of their materials, their manufacturing processes, the gripping technologies and the proposed control methods. Finally, the challenges that have to be overcome to boost its definitive implementation in the real world are highlighted. Therefore, this review intends to serve as a guide for those researchers working in the field of soft robotics for Agriculture 4.0, and more specifically, in the design of soft grippers for fruit harvesting robots.

The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1α signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1α endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1α to catalyze RIDD. The protective role of IRE1α under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis. IRE1α plays a key role in the unfolded protein response (UPR) by promoting the unconventional splicing of the XBP1 and the selective cleavage of RNAs. Here the authors report that IRE1α is activated upon the DNA damage response and selectively controls the stability of mRNAs to maintain genome integrity.

In the movement for global health equity, increased research and funding have not yet addressed a shortage of evidence on effectively implementing context-specific interventions; one unmet need is facilitating access to specialty care within the public health sector in Mexico. Compañeros en Salud has been piloting a novel program, called Right to Healthcare (RTHC), to increase access to specialty care for the rural poor in Chiapas, Mexico. The RTHC program incorporates social work, patient navigation, referrals, direct economic support, and accompaniment for patients. This study evaluates the effectiveness of the RTHC program. Primary outcomes analyzed included acceptance of any referral and attendance of any appointment. Secondary outcomes included acceptance of the first referral and rate of appointment attendance for patients with an accepted referral. Using referral process data for the years 2014 to 2019 from a public tertiary care hospital in Chiapas, 91 RTHC patients were matched using 2:1 optimal pair matching with a control cohort balancing covariates of patient age, sex, specialty referred to, level of referring hospital, and municipality. RTHC patients were more likely to have had an accepted referral (OR 17.42, 95% CI 3.68 to 414.16) and to have attended an appointment (OR 5.49, 95% CI 2.93 to 11.60) compared to the matched control group. RTHC patients were also more likely to have had their first referral accepted (OR 2.78, 95% CI 1.29 to 6.73). Among patients with an accepted referral, RTHC patients were more likely to have attended an appointment (OR 3.86, 95% CI 1.90 to 8.57). The results demonstrate that the RTHC model is successful in increasing access to specialty care by both increasing referral acceptance and appointment attendance.

Perkinsus marinus , a parasite myzozoa native from the Atlantic Ocean, has spread across various bivalve species in the Pacific Ocean. In the Gulf of California, clams like Larkinia grandis and Leukoma grata have become a secondary fishery, experiencing demand. During annual sampling (August 2017 − July 2018, n  = 30/month), the Ray’s fluid thioglycollate medium (RFTM) revealed presumptive hypnospores of Perkinsus sp. in L. grandis , with a low parasite prevalence (4.16%) and density (≤ 3.14 hypnospores g −1 tissue). From summer 2020 to summer 2021, P. marinus was seasonally identified in L. grata via staining and PCR tests, showing mean prevalence and density of 48.33% and 48 hypnospores g −1 tissue, respectively. The infection level was light in both clams. This parasite’s presence in these new hosts within the southeastern Gulf of California confirms its ability to expand into non-native places, signaling a need for intervention strategies in managing and transporting mollusk species within the region.

Bromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months’ duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8–33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0–8.6) and a CBR of 31.7% (95% CI, 18.1–48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents. Bromodomain and extraterminal proteins (BET) are reported as targets for anticancer therapy. Here, the authors report the final results of a phase I clinical trial of the BET inhibitor trotabresib in patients with solid tumours and diffuse large B-cell lymphoma.

This research proposes a new distribution system of goods in the historical center of the city of Santiago, Chile. For the design of the urban logistic system, the methodology city logistics and last mile are used. This design incorporates to the freight transport flexible solutions that improve the efficiency of the distribution process and trade supply, minimizing the environmental impact of the atmospheric pollution (AP). The proposal was made through the data collection, the characterization of the sector and the diagnosis of the urban logistics processes. The analysis of the factors allowed to evaluate the costs of the AP negative externalities. The causes were used as design criteria for the proposals, with the aim of improving the quality of life of the city users. The physical location selection of the Cross-Docking was made through an optimization model of maximum coverage. The optimization algorithm of the nearest neighbor was proposed for vehicle routing. The analytic hierarchy process (AHP) was used to generate a ranking of the best non-polluting vehicles to be used in the zone. Finally, the results obtained allowed a 53 ton decrease in carbon dioxide in the square kilometer and reduced 1103 h of interruptions per year in the vehicular congestion of the sector.

Background Crohn’s disease is one of the two categories of inflammatory bowel diseases that affect the gastrointestinal tract. The heritability estimate has been reported to be 0.75. Several genes linked to Crohn’s disease risk have been identified using a plethora of strategies such as linkage-based studies, candidate gene association studies, and lately through genome-wide association studies (GWAS). Nevertheless, to our knowledge, a compendium of all the genes that have been associated with CD is lacking. Methods We conducted functional analyses of a gene set generated from a systematic review where genes potentially related to CD found in the literature were analyzed and classified depending on the genetic evidence reported and putative biological function. For this, we retrieved and analyzed 2496 abstracts comprising 1067 human genes plus 22 publications regarding 133 genes from GWAS Catalog. Then, each gene was curated and categorized according to the type of evidence associated with Crohn’s disease. Results We identified 126 genes associated with Crohn’s disease risk by specific experiments. Additionally, 71 genes were recognized associated through GWAS alone, 18 to treatment response, 41 to disease complications, and 81 to related diseases. Bioinformatic analysis of the 126 genes supports their importance in Crohn’s disease and highlights genes associated with specific aspects such as symptoms, drugs, and comorbidities. Importantly, most genes were not included in commercial genetic panels suggesting that Crohn’s disease is genetically underdiagnosed. Conclusions We identified a total of 126 genes from PubMed and 71 from GWAS that showed evidence of association to diagnosis, 18 to treatment response, and 41 to disease complications in Crohn’s disease. This prioritized gene catalog can be explored at http://victortrevino.bioinformatics.mx/CrohnDisease .