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The results of a phase I trial assessing a personal neoantigen multi-peptide vaccine in patients with melanoma, showing feasibility, safety, and immunogenicity. Personalized cancer vaccine trials Neoantigens have long been considered optimal targets for anti-tumour vaccines, and recent mutation coding and prediction techniques have aimed to streamline their identification and selection. Two papers in this issue report results from personalized neoantigen vaccine trials in patients with cancer. Catherine Wu and colleagues report the results of a phase I trial of a personalized cancer vaccine that targets up to 20 patient neoantigens. The vaccine was safe and induced tumour-antigen-specific immune responses. Four out of six patients treated showed no recurrence at 25 months, and progressing patients responded to further therapy with checkpoint inhibitor. Ugur Sahin and colleagues report the first-in-human application of a personalized neoantigen vaccine in patients with melanoma. Their vaccination strategy includes sequencing and computational identification of neoantigens from patients, and design and manufacture of a poly-antigen RNA vaccine for treatment. In 13 patients, the vaccine boosted immunity against some of the selected tumour antigens from the individual patients, and two patients showed infiltration of tumour-reactive T cells. These results suggest that personalized vaccines could be refined and tailored to provide clinical benefit as cancer immunotherapies. Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens 1 , a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response 2 , their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4 + and CD8 + T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.

Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13-41%) and 20% for PDAC (five of 25; 95% CI, 7-41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19-58%) in CRC and 29% (five of 17; 95% CI, 10-56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of the HERVK repeat RNA in patients with disease control. This study provides proof of concept of combining radiation with immune checkpoint blockade in immunotherapy-resistant cancers.

Abstract Context Hypoglycemia in people with diabetes is common, especially in those taking medications such as insulin and sulfonylureas (SU) that place them at higher risk. Hypoglycemia is associated with distress in those with diabetes and their families, medication nonadherence, and disruption of life and work, and it leads to costly emergency department visits and hospitalizations, morbidity, and mortality. Objective To review and update the diabetes-specific parts of the 2009 Evaluation and Management of Adult Hypoglycemic Disorders: Endocrine Society Clinical Practice Guideline and to address developing issues surrounding hypoglycemia in both adults and children living with diabetes. The overriding objectives are to reduce and prevent hypoglycemia. Methods A multidisciplinary panel of clinician experts, together with a patient representative, and methodologists with expertise in evidence synthesis and guideline development, identified and prioritized 10 clinical questions related to hypoglycemia in people living with diabetes. Systematic reviews were conducted to address all the questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. Results The panel agreed on 10 questions specific to hypoglycemia risk and prevention in people with diabetes for which 10 recommendations were made. The guideline includes conditional recommendations for use of real-time continuous glucose monitoring (CGM) and algorithm-driven insulin pumps in people with type 1 diabetes (T1D), use of CGM for outpatients with type 2 diabetes at high risk for hypoglycemia, use of long-acting and rapid-acting insulin analogs, and initiation of and continuation of CGM for select inpatient populations at high risk for hypoglycemia. Strong recommendations were made for structured diabetes education programs for those at high risk for hypoglycemia, use of glucagon preparations that do not require reconstitution vs those that do for managing severe outpatient hypoglycemia for adults and children, use of real-time CGM for individuals with T1D receiving multiple daily injections, and the use of inpatient glycemic management programs leveraging electronic health record data to reduce the risk of hypoglycemia. Conclusion The recommendations are based on the consideration of critical outcomes as well as implementation factors such as feasibility and values and preferences of people with diabetes. These recommendations can be used to inform clinical practice and health care system improvement for this important complication for people living with diabetes.

Systemic inflammation is central to aging‐related conditions. However, the intrinsic factors that induce inflammation are not well understood. We previously identified a cell‐autonomous pathway through which damaged nuclear DNA is trafficked to the cytosol where it activates innate cytosolic DNA sensors that trigger inflammation. These results led us to hypothesize that DNA released after cumulative damage contributes to persistent inflammation in aging cells through a similar mechanism. Consistent with this notion, we found that older cells harbored higher levels of extranuclear DNA compared to younger cells. Extranuclear DNA was exported by a leptomycin B‐sensitive process, degraded through the autophagosome–lysosomal pathway and triggered innate immune responses through the DNA‐sensing cGAS‐STING pathway. Patient cells from the aging diseases ataxia and progeria also displayed extranuclear DNA accumulation, increased pIRF3 and pTBK1, and STING‐dependent p16 expression. Removing extranuclear DNA in old cells using DNASE2A reduced innate immune responses and senescence‐associated (SA) β‐gal enzyme activity. Cells and tissues of Dnase2a−/− mice with defective DNA degradation exhibited slower growth, higher activity of β‐gal, or increased expression of HP‐1β and p16 proteins, while Dnase2a−/−;Sting−/− cells and tissues were rescued from these phenotypes, supporting a role for extranuclear DNA in senescence. We hypothesize a direct role for excess DNA in aging‐related inflammation and in replicative senescence, and propose DNA degradation as a therapeutic approach to remove intrinsic DNA and revert inflammation associated with aging.

The aim was to evaluate the impact of bariatric surgery on cardiac and sudomotor autonomic C-fiber function in obese subjects with and without Type 2 diabetes mellitus (T2DM), using sudorimetry and heart rate variability (HRV) analysis. Patients were evaluated at baseline, 4, 12 and 24 weeks after vertical sleeve gastrectomy or Roux-en-Y gastric bypass. All subjects were assessed using SudoscanTM to measure electrochemical skin conductance (ESC) of hands and feet, time and frequency domain analysis of HRV, Neurologic Impairment Scores of lower legs (NIS-LL), quantitative sensory tests (QST) and sural nerve conduction studies. Seventy subjects completed up to 24-weeks of follow-up (24 non-T2DM, 29 pre-DM and 17 T2DM). ESC of feet improved significantly towards normal in T2DM subjects (Baseline = 56.71±3.98 vs 12-weeks = 62.69±3.71 vs 24-weeks = 70.13±2.88, p<0.005). HRV improved significantly in T2DM subjects (Baseline sdNN (sample difference of the beat to beat (NN) variability) = 32.53±4.28 vs 12-weeks = 44.94±4.18 vs 24-weeks = 49.71±5.19, p<0,001 and baseline rmsSD (root mean square of the difference of successive R-R intervals) = 23.88±4.67 vs 12-weeks = 38.06±5.39 vs 24-weeks = 43.0±6.25, p<0.0005). Basal heart rate (HR) improved significantly in all groups, as did weight, body mass index (BMI), percent body fat, waist circumference and high-density lipoprotein (HDL). Glycated hemoglobin (HbA1C), insulin and HOMA2-IR (homeostatic model assessment) levels improved significantly in pre-DM and T2DM subjects. On multiple linear regression analysis, feet ESC improvement was independently associated with A1C, insulin and HOMA2-IR levels at baseline, and improvement in A1C at 24 weeks, after adjusting for age, gender and ethnicity. Sudomotor function improvement was not associated with baseline weight, BMI, % body fat or lipid levels. Improvement in basal HR was also independently associated with A1C, insulin and HOMA2-IR levels at baseline. This study shows that bariatric surgery can restore both cardiac and sudomotor autonomic C-fiber dysfunction in subjects with diabetes, potentially impacting morbidity and mortality.

The crayfish plague pathogen Aphanomyces astaci (Oomycota: Saprolegniales) is native to North America but expanded with its crayfish hosts to other regions. In most of its invaded range, A. astaci haplotypes are associated with specific American crayfish, probably due to introduction bottlenecks, but haplotype diversity is higher and clear host-specific associations are lacking in its native range. However, little is known about the infection rate and load of this pathogen in North America. We investigated the distribution, prevalence and genetic variation of A. astaci in Pennsylvania (eastern USA), where multiple native and introduced crayfish species (family Cambaridae) occur. We used A. astaci -specific quantitative PCR to screen 533 individuals representing 8 crayfish species (2 Cambarus and 6 Faxonius ) from 49 sites. Faxonius limosus , an American species first introduced to Europe and carrier of A. astaci genotype group E, was of particular interest. We confirmed A. astaci infections in 76% of sites in all but 1 host taxon, with the pathogen infection rate and load comparable to established populations of North American crayfish studied in Europe and Japan. Despite the absence of highly infected hosts, we genotyped A. astaci from 14 sites. We only detected 2 mitochondrial haplotypes, but nuclear markers indicated the presence of at least 4 distinct pathogen genotypes, none documented from invaded areas in Europe or Asia. Genotype group E was not detected in F. limosus , possibly due to limited spatial distribution of the original strain. Our results highlight both benefits and limitations of combining multiple pathogen genotyping methods.

Invasive crayfish are considered a serious threat to native crayfish and other aquatic organisms in North America. Here, we report what is, to our knowledge, the first formal documentation of Procambarus clarkii (Girard) (Red Swamp Crayfish) within the Susquehanna River basin in the eastern US. We collected 9 individuals consisting of multiple size classes (indicative of an established population) from a small public fishing pond situated in a wetland complex in Lycoming County, PA, adjacent to a tributary of the West Branch Susquehanna River. We speculate that this population was introduced via live bait, aquarium release, or commercial sportfish stocking. Red Swamp Crayfish may have adverse ecological impacts if further spread continues within the Susquehanna River basin.

Cambarus sp. C is a poorly understood group of morphologically similar crayfishes whose range extends along North America's Atlantic Slope from South Carolina northward to Pennsylvania. In Pennsylvania, C. sp. C occurs in the lower Delaware River basin west of Philadelphia but has never been found to the east of the city. In October 2024, during ongoing surveys of eastern Pennsylvania, we discovered C. sp. C in tributaries of the lower Delaware River east of Philadelphia. One of the tributaries flows into the river from Pennsylvania (Bucks County), while 2 others flow into the river from New Jersey (Mercer County). Herein, we describe these collections, which expand the range of C. sp. C by ~45 km to the east and add a new crayfish species to New Jersey and possibly Pennsylvania, improving our understanding of the crayfish fauna of the mid-Atlantic region of North America.

Abstract Context Interventions targeting hypoglycemia in people with diabetes are important for improving quality of life and reducing morbidity and mortality. Objective To support development of the Endocrine Society Clinical Practice Guideline for management of individuals with diabetes at high risk for hypoglycemia. Methods We searched several databases for studies addressing 10 questions provided by a guideline panel from the Endocrine Society. Meta-analysis was conducted when feasible. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess certainty of evidence. Results We included 149 studies reporting on 43 344 patients. Continuous glucose monitoring (CGM) reduced episodes of severe hypoglycemia in patients with type 1 diabetes (T1D) and reduced the proportion of patients with hypoglycemia (blood glucose [BG] levels <54 mg/dL). There were no data on use of real-time CGM with algorithm-driven insulin pumps vs multiple daily injections with BG testing in people with T1D. CGM in outpatients with type 2 diabetes taking insulin and/or sulfonylureas reduced time spent with BG levels under 70 mg/dL. Initiation of CGM in hospitalized patients at high risk for hypoglycemia reduced episodes of hypoglycemia with BG levels lower than 54 mg/dL and time spent under 54 mg/dL. The proportion of patients with hypoglycemia with BG levels lower than 70 mg/dL and lower than 54 mg/dL detected by CGM was significantly higher than point-of-care BG testing. We found no data evaluating continuation of personal CGM in the hospital. Use of an inpatient computerized glycemic management program utilizing electronic health record data was associated with fewer patients with and episodes of hypoglycemia with BG levels lower than 70 mg/dL and fewer patients with severe hypoglycemia compared with standard care. Long-acting basal insulin analogs were associated with less hypoglycemia. Rapid-acting insulin analogs were associated with reduced severe hypoglycemia, though there were more patients with mild to moderate hypoglycemia. Structured diabetes education programs reduced episodes of severe hypoglycemia and time below 54 mg/dL in outpatients taking insulin. Glucagon formulations not requiring reconstitution were associated with longer times to recovery from hypoglycemia, although the proportion of patients who recovered completely from hypoglycemia was not different between the 2 groups. Conclusion This systematic review summarized the best available evidence about several interventions addressing hypoglycemia in people with diabetes. This evidence base will facilitate development of clinical practice guidelines by the Endocrine Society.

(1) Background: Adenosquamous carcinoma (ASC) is a rare subtype of colon cancer. Its rarity makes characterization challenging, although colonic ASC is believed to present at more advanced stages and have worse outcomes versus adenocarcinoma. This study aims to characterize the clinicopathological characteristics and clinical outcomes of colonic ASC. (2) Methods: This is a single-center, retrospective review of patients diagnosed with colonic ASC from 2000 to 2020. Data extracted included patient demographics, staging at diagnosis, tumor clinicopathologic and genetic characteristics, and clinical outcomes. (3) Results: Among 61,126 patients with colorectal cancer, 13 (0.02%) had colonic ASC, with a mean age at diagnosis of 48.7 years. The cecum/ascending colon was the most common primary site (6/13, 46.2%), and all except one patient was diagnosed with Stage III or IV disease. Among the eight patients with mismatch repair genetics available, only one was mismatch repair deficient. Eleven patients (84.6%) underwent surgery, and 11 likewise received some form of chemotherapy. Recurrence occurred in 7 of 13 patients (53.8%), and the overall five-year survival rate was 38.5%. The median survival rate was 39.4 months overall (30.5 months for Stage III, 23.7 months for Stage IV). (4) Conclusions: Overall, colonic ASC is rare, and this cohort of colonic ASC patients demonstrated advanced stage at diagnosis, frequent recurrence, and poor overall survival. Additional research remains to compare these characteristics with those of comparably staged adenocarcinoma and to develop specific management recommendations.