HER2 overexpression in urothelial carcinoma with GATA3 and PPARG copy number gains.

HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.

Cysteine-binding adjuvant enhances survival and promotes immune function in a murine model of acute myeloid leukemia.

ABSTRACT: Therapeutic vaccination has long been a promising avenue for cancer immunotherapy but is often limited by tumor heterogeneity. The genetic and molecular diversity between patients often results in variation in the antigens present on cancer cell surfaces. As a result, recent research has focused on personalized cancer vaccines. Although promising, this strategy suffers from time-consuming production, high cost, inaccessibility, and targeting of a limited number of tumor antigens. Instead, we explore an antigen-agnostic polymeric in situ cancer vaccination platform for treating blood malignancies, in our model here with acute myeloid leukemia (AML). Rather than immunizing against specific antigens or targeting adjuvant to specific cell-surface markers, this platform leverages a characteristic metabolic and enzymatic dysregulation in cancer cells that produces an excess of free cysteine thiols on their surfaces. These thiols increase in abundance after treatment with cytotoxic agents such as cytarabine, the current standard of care in AML. The resulting free thiols can undergo efficient disulfide exchange with pyridyl disulfide (PDS) moieties on our construct and allow for in situ covalent attachment to cancer cell surfaces and debris. PDS-functionalized monomers are incorporated into a statistical copolymer with pendant mannose groups and TLR7 agonists to target covalently linked antigen and adjuvant to antigen-presenting cells in the liver and spleen after IV administration. There, the compound initiates an anticancer immune response, including T-cell activation and antibody generation, ultimately prolonging survival in cancer-bearing mice.

A systematic review on sonoelastography for rotator-cuff post-repair assessment.

Surgical repair of rotator cuff tears is performed routinely; however, the risks of re-tears and the associated consequences are significant. Sonoelastography, an imaging modality that evaluates the mechanical properties of tissues, can examine the dynamic transitions in rotator cuff stiffness following retear and investigate the relationship between these changes and the occurrences of retears. This systematic review aimed to summarize the role of perioperative sonoelastography in repaired rotator cuffs. A comprehensive search of the PubMed, Embase, and Cochrane databases was conducted, covering studies published until June 19, 2023. The Newcastle-Ottawa scale was used for quality assessment. The key information extracted from each study included the injury/surgery type, follow-up duration, sonoelastography mode, and main sonoelastographic findings. Eleven eligible studies comprising 355 patients were included. All studies focused on supraspinatus muscles and tendons with previous arthroscopic repairs. During the postoperative 1st - 6th months, muscle stiffness increased in the supraspinatus and decreased in the ipsilateral deltoid. Failure to recover supraspinatus muscle elasticity might be indicative of potential tendon re-tear; however, it is imperative to first establish correlations with other imaging modalities. Conflicting findings have been observed regarding stiffening or softening of the supraspinatus tendon after surgical repair. The preoperative stiffness of the supraspinatus tendon did not correlate with postoperative tendon integrity or function.

Ultrasound-guided injection of the achilles paratenon: A cadaveric investigation.

BACKGROUND: Injections around the Achilles tendon (AT) are commonly performed in clinical practice to manage non-insertional Achilles tendinopathy, but the presence/distribution of the injectate with relation to its sheath has not been assessed specifically. Accordingly, the aim of this cadaveric investigation was to demonstrate the feasibility of Achilles paratenon injection under ultrasound guidance - by confirming the exact needle positioning as well as the dye distribution inside the paratenon lumen. METHODS: A descriptive laboratory study with three human cadaveric specimens (one fresh cadaver and two cadavers embalmed using the Fix for Life (F4L) method) was performed in a tertiary-care academic institution. The interventional technique and the related anatomical findings were illustrated. During the injection, the needle was advanced inside the Achilles paratenon under ultrasound guidance i.e. in-plane medial-to-lateral approach. With the objective to confirm its correct placement, the needle was kept in situ on the right AT of the fresh cadaver. Likewise, to demonstrate the location of the dye inside the lumen of Achilles paratenon, the other five ATs - four on the embalmed cadavers and one on the fresh cadaver - were injected with 5 mL of green color dye. After removal of the needle, a layer-by-layer anatomical dissection was performed on all three cadavers. RESULTS: On the right AT of the fresh cadaver, the position of the needle's tip within the Achilles paratenon was confirmed. Accurate placement of the dye inside the paratenon lumen was confirmed in four (80%) ATs, one of the fresh and three of the embalmed cadavers. No spread inside the crural fascia compartment or between the AT and the Kager's fat pad was observed. Herewith, unintentional spilling of the dye within the superficial soft tissues of the posterior leg was reported in the left AT of one of the two embalmed cadavers (20%). CONCLUSIONS: Ultrasound-guided injection using the in-plane, medial-to-lateral approach can accurately target the lumen of Achilles paratenon.

CT Colonography Reporting and Data System (C-RADS): Version 2023 Update.

The CT Colonography Reporting and Data System (C-RADS) has withstood the test of time and proven to be a robust classification scheme for CT colonography (CTC) findings. C-RADS version 2023 represents an update on the scheme used for colorectal and extracolonic findings at CTC. The update provides useful insights gained since the implementation of the original system in 2005. Increased experience has demonstrated confusion on how to classify the mass-like appearance of the colon consisting of soft tissue attenuation that occurs in segments with acute or chronic diverticulitis. Therefore, the update introduces a new subcategory, C2b, specifically for mass-like diverticular strictures, which are likely benign. Additionally, the update simplifies extracolonic classification by combining E1 and E2 categories into an updated extracolonic category of E1/E2 since, irrespective of whether a finding is considered a normal variant (category E1) or an otherwise clinically unimportant finding (category E2), no additional follow-up is required. This simplifies and streamlines the classification into one category, which results in the same management recommendation.

Sociodemographic Factors and Screening CT Colonography Use Among Medicare Beneficiaries.

BACKGROUND. Approximately one-third of the eligible U.S. population have not undergone guideline-compliant colorectal cancer (CRC) screening. Guidelines recognize various screening strategies to increase adherence. CMS provides coverage for all recommended screening tests except CT colonography (CTC). OBJECTIVE. The purpose of this study was to compare CTC and other CRC screening tests in terms of associations of utilization with income, race and ethnicity, and urbanicity in Medicare fee-for-service beneficiaries. METHODS. This retrospective study used CMS Research Identifiable Files from January 1, 2011, through December 31, 2020. These files contain claims information for 5% of Medicare fee-for-service beneficiaries. Data were extracted for individuals 45-85 years old, and individuals with high CRC risk were excluded. Multivariable logistic regression models were constructed to determine the likelihood of undergoing CRC screening tests (as well as of undergoing diagnostic CTC, a CMS-covered test with similar physical access as screening CTC) as a function of income, race and ethnicity, and urbanicity while controlling for sex, age, Charlson comorbidity index, U.S. census region, screening year, and related conditions and procedures. RESULTS. For 12,273,363 beneficiary years (mean age, 70.5 ± 8.2 [SD] years; 2,436,849 unique beneficiaries: 6,774,837 female beneficiaries, 5,498,526 male beneficiaries), there were 785,103 CRC screenings events, including 645 for screening CTC. Compared with individuals living in communities with per capita income of less than US$25,000, individuals in communities with income of US$100,000 or more had OR for undergoing screening CTC of 5.73, optical colonoscopy (OC) of 1.36, sigmoidoscopy of 1.03, guaiac fecal occult blood test or fecal immunochemical test of 1.50, stool DNA of 1.43, and diagnostic CTC of 2.00. The OR for undergoing screening CTC was 1.00 for Hispanic individuals and 1.08 for non-Hispanic Black individuals compared with non-Hispanic White individuals. Compared with the OR for undergoing screening CTC for residents of metropolitan areas, the OR was 0.51 for residents of micropolitan areas and 0.65 for residents of small or rural areas. CONCLUSION. The association with income was substantially larger for screening CTC than for other CRC screening tests or for diagnostic CTC. CLINICAL IMPACT. Medicare's noncoverage for screening CTC may contribute to lower adherence with CRC screening guidelines for lower-income beneficiaries. Medicare coverage of CTC could reduce income-based disparities for individuals avoiding OC owing to invasiveness, need for anesthesia, or complication risk.

Foodborne and airborne polyethersulfone nanoplastics respectively induce liver and lung injury in mice: Comparison with microplastics.

Micro/nanoplastics (MNP) are ubiquitous in the environment and multiple living organisms. The toxicity of some common types of MNP, e.g., polyethersulfone (PES) MNP, remains poorly understood. Multi-omics approaches were used in this study to determine the effects of foodborne and airborne PES MNP on liver and lung, respectively. Foodborne MNP were capable of inducing gut microbial dysbiosis, gut and serum metabolic disruption, and liver transcriptomic dysregulation, and affecting serum antioxidant activity and liver function, resulting in liver injury. As for the airborne MNP, they were found to induce nasal and lung microbial dysbiosis, serum and lung metabolic disruption, and liver transcriptome disturbance, and cause disrupted serum antioxidant activity and lung injury. Foodborne and airborne PES NP were found to respectively induce greater liver and lung toxicity than MP, which could be associated with the differences between NP and MP exposures. The relevant results suggest that foodborne PES MNP could disrupt the "gut microbiota-gut-liver" axis and induce hepatic injury, while airborne PES MNP could affect the "airborne microbiota-lung" axis and cause lung injury. The findings could benefit the diagnoses of liver and lung injury respectively induced by foodborne and airborne PES MNP, as well as the proper use of PES in human living environment.

Engineered IL-7 synergizes with IL-12 immunotherapy to prevent T cell exhaustion and promote memory without exacerbating toxicity.

Cancer immunotherapy is moving toward combination regimens with agents of complementary mechanisms of action to achieve more frequent and robust efficacy. However, compared with single-agent therapies, combination immunotherapies are associated with increased overall toxicity because the very same mechanisms also work in concert to enhance systemic inflammation and promote off-tumor toxicity. Therefore, rational design of combination regimens that achieve improved antitumor control without exacerbated toxicity is a main objective in combination immunotherapy. Here, we show that the combination of engineered, tumor matrix-binding interleukin-7 (IL-7) and IL-12 achieves remarkable anticancer effects by activating complementary pathways without inducing any additive immunotoxicity. Mechanistically, engineered IL-12 provided effector properties to T cells, while IL-7 prevented their exhaustion and boosted memory formation as assessed by tumor rechallenge experiments. The dual combination also rendered checkpoint inhibitor (CPI)-resistant genetically engineered melanoma model responsive to CPI. Thus, our approach provides a framework of evaluation of rationally designed combinations in immuno-oncology and yields a promising therapy.

Enhanced serum levels of tumor necrosis factor-α, interleukin-1ß, and -6 in sarcopenia: alleviation through exercise and nutrition intervention.

BACKGROUND: Limited research has been conducted on the post-intervention inflammatory status in sarcopenic patients, despite previous studies revealing elevated pro-inflammatory markers. This study aimed to investigate the potential elevation of specific pro-inflammatory cytokines in sarcopenic patients and evaluate the effects of exercise and nutritional support interventions on these cytokine levels. METHODS: In this post-hoc analysis of a randomized controlled trial (RCT), 57 individuals with sarcopenia from the RCT and 57 non-sarcopenic participants from the same geriatric community cohort that did not participate in the RCT were enrolled. Grip strength and body composition measurements were recorded. Tumor necrotizing factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-15 levels were assessed at baseline for both groups and after a 12-week intervention consisting of resistive exercise and supplementation with branched-chain amino acids, calcium, and vitamin D3 in the patients with sarcopenia. RESULTS: The sarcopenic group demonstrated significantly lower body weight, body mass index, grip strength, and skeletal muscle mass index. Moreover, sarcopenic patients exhibited higher levels of TNF-α (p=0.007), IL-1ß (p<0.001), and IL-6 (p<0.001), while no significant difference was observed in IL-15 (p=0.345) between participants with and those without sarcopenia. Following the intervention, the sarcopenic group experienced significant improvements in grip strength and skeletal muscle mass index with a notable reduction in TNF-α (p=0.003), IL-1ß (p=0.012) and IL-6 (p=0.001) levels. CONCLUSIONS: Sarcopenic patients exhibit elevated levels of TNF-α, IL-1ß, and IL-6, which declined after nutrition support and exercise interventions. However, further research is necessary to evaluate the long-term impact of these interventions on cytokine levels.

Shedding light on rare iliac crest pain: exploring iliohypogastric nerve schwannoma using ultrasound imaging.

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Membrane-localized neoantigens predict the efficacy of cancer immunotherapy.

Immune checkpoint immunotherapy (ICI) can re-activate immune reactions against neoantigens, leading to remarkable remission in cancer patients. Nevertheless, only a minority of patients are responsive to ICI, and approaches for prediction of responsiveness are needed to improve the success of cancer treatments. While the tumor mutational burden (TMB) correlates positively with responsiveness and survival of patients undergoing ICI, the influence of the subcellular localizations of the neoantigens remains unclear. Here, we demonstrate in both a mouse melanoma model and human clinical datasets of 1,722 ICI-treated patients that a high proportion of membrane-localized neoantigens, particularly at the plasma membrane, correlate with responsiveness to ICI therapy and improved overall survival across multiple cancer types. We further show that combining membrane localization and TMB analyses can enhance the predictability of cancer patient response to ICI. Our results may have important implications for establishing future clinical guidelines to direct the choice of treatment toward ICI.

The impact of shoulder pathologies on job discontinuation and return to work: a pilot ultrasonographic investigation.

BACKGROUND: Ultrasound imaging has emerged as one of the most useful tools for evaluating shoulder disorders. To date, the association between shoulder ultrasonography and a patient's work status has rarely been explored by antecedent studies. AIM: This study aimed to investigate the association between sonographically diagnosed shoulder pathologies and job discontinuation and return to work. DESIGN: A cross-sectional study. SETTING: Outpatient clinic in the university hospital. POPULATION: Fifty-nine patients who were older than 20 years of age and had worked in a full-time job within the past three years. METHODS: All participants underwent clinical evaluation using the visual analog scale (for pain), Shoulder Pain and Disability Index, Pittsburgh Sleep Quality Index, and shoulder ultrasound examination. The work-related ergonomic risks, including dealing with heavy objects, repeated use and requiring forceful motion of the affected upper extremity, were assessed. The ultrasound-identified shoulder pathologies associated with job discontinuation, that is, sick leave due to painful shoulder for more than two consecutive months, were considered as the primary outcome. In the job discontinuation subgroup, we further investigated the association between return to work and the clinical/sonographic findings. RESULTS: Univariate analysis revealed a positive association between job discontinuation and shoulder surgery or work types requiring forceful upper-limb movements. Multivariate analysis demonstrated that job discontinuation was positively associated with supraspinatus tendon full-thickness tears (risk ratio, 8.80; 95% CI, 1.77-10.56; P=0.018). Of the patients who received shoulder surgery, 46.6% had recurrent rotator cuff tears. Return to work was likely to be related to pain scores during overhead activities and shoulder function impairment but not to sonographic findings. CONCLUSIONS: Job discontinuation is associated with shoulder surgery, work that necessitates forceful upper-extremity movements and supraspinatus tendon full-thickness tears detected by ultrasound. CLINICAL REHABILITATION IMPACT: Sonographic findings should not be used as the only standard for evaluating the patient's work capability.

Enhancing diagnosis and treatment of superior cluneal nerve entrapment: cadaveric, clinical, and ultrasonographic insights.

OBJECTIVES: Low back pain is a prevalent public health issue caused by superior cluneal nerve (SCN) entrapment. This study aimed to explore the course of SCN branches, cross-sectional area (CSA) of the nerves, and effects of ultrasound-guided SCN hydrodissection. METHODS: SCN distance relative to the posterior superior iliac spines was measured and compared with ultrasound findings in asymptomatic volunteers. The CSA of the SCN, pressure-pain threshold, and pain measurements were obtained from asymptomatic controls and patients with SCN entrapment at various time points after hydrodissection (with 1 mL of 50% dextrose, 4 mL of 1% lidocaine, and 5 mL of 1% normal saline) in the short-axis view. RESULTS: Twenty sides of 10 formalin-fixed cadavers were dissected. The SCN locations on the iliac crest did not differ from the ultrasound findings in 30 asymptomatic volunteers. The average CSA of the SCN across different branches and sites ranged between 4.69-5.67 mm2 and did not vary across different segments/branches or pain statuses. Initial treatment success was observed in 77.7% (n = 28) of 36 patients receiving hydrodissection due to SCN entrapment. A group with initial treatment success experienced symptom recurrence in 25% (n = 7) of cases, and those with recurrent pain had a higher prevalence of scoliosis than those without symptom recurrence. CONCLUSIONS: Ultrasonography effectively localizes SCN branches on the iliac crest, whereby increased nerve CSA is not useful for diagnosis. Most patients benefit from ultrasound-guided dextrose hydrodissection; however, those with scoliosis may experience symptom recurrence and whether structured rehabilitation can reduce recurrence post-injection should be considered as one perspective in future research. Trial registration ClinicalTrials.gov (NCT04478344). Registered on 20 July 2020, https://clinicaltrials.gov/ct2/show/NCT04478344?cond=Superior+Cluneal+Nerve&cntry=TW&draw=2&rank=1 . Critical relevance statement Ultrasound imaging accurately locates SCN branches on the iliac crest, while enlargement of the CSA is not useful in diagnosing SCN entrapment; however, approximately 80% of SCN entrapment cases respond positively to ultrasound-guided dextrose hydrodissection.

Imaging of colon and rectal cancer.

Colon and rectal cancer imaging has traditionally been performed to assess for distant disease (typically lung and liver metastases) and to assess the resectability of the primary tumor. With technological and scientific advances in imaging and the evolution of treatment options, the role of imaging has expanded. Radiologists are now expected to provide a precise description of primary tumor invasion extent, including adjacent organ invasion, involvement of the surgical resection plane, extramural vascular invasion, lymphadenopathy, and response to neoadjuvant treatment, and to monitor for recurrence after clinical complete response.

Semimembranosus muscle tear masquerading as a hypervascular tumor: ultrasonographic differential diagnosis for gluteal pain syndrome.

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