PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness.

BACKGROUND: Recently approved treatments and updates to genetic testing recommendations for prostate cancer have created a need for correlated analyses of patient outcomes data via germline genetic mutation status. Genetic registries address these gaps by identifying candidates for recently approved targeted treatments, expanding clinical trial data examining specific gene mutations, and understanding effects of targeted treatments in the real-world setting. METHODS: The PROMISE Registry is a 20-year (5-year recruitment, 15-year follow-up), US-wide, prospective genetic registry for prostate cancer patients. Five thousand patients will be screened through an online at-home germline testing to identify and enroll 500 patients with germline mutations, including: pathogenic or likely pathogenic variants and variants of uncertain significance in genes of interest. Patients will be followed for 15 years and clinical data with real time patient reported outcomes will be collected. Eligible patients will enter long-term follow-up (6-month PRO surveys and medical record retrieval). As a virtual study with patient self-enrollment, the PROMISE Registry may fill gaps in genetics services in underserved areas and for patients within sufficient insurance coverage. RESULTS: The PROMISE Registry opened in May 2021. 2114 patients have enrolled to date across 48 US states and 23 recruiting sites. 202 patients have met criteria for long-term follow-up. PROMISE is on target with the study's goal of 5000 patients screened and 500 patients eligible for long-term follow-up by 2026. CONCLUSIONS: The PROMISE Registry is a novel, prospective, germline registry that will collect long-term patient outcomes data to address current gaps in understanding resulting from recently FDA-approved treatments and updates to genetic testing recommendations for prostate cancer. Through inclusion of a broad nationwide sample, including underserved patients and those unaffiliated with major academic centers, the PROMISE Registry aims to provide access to germline genetic testing and to collect data to understand disease characteristics and treatment responses across the disease spectrum for prostate cancer with rare germline genetic variants.

Heart transplantation from COVID-positive donors with 6-month follow-up: A case series.

BACKGROUND: Data on long term outcomes in heart transplant recipients from Coronavirus disease 2019 (COVID-19) positive donors are limited. METHODS AND RESULTS: We present a series of nine patients who underwent heart transplants from COVID-19 PCR-positive donors between November 2021 to August 2022 with mean follow-up of 12.12 ± 3 months. All the recipients received two doses of COVID-19 vaccine and had at least 6 months follow-up. Eight recipients had acceptable long-term outcomes; one patient died during index admission from primary graft dysfunction. Details regarding donor and recipient characteristics, management and outcomes are provided. Two patients developed deep vein thrombosis, and one patient underwent pacemaker implantation for sinus node dysfunction. Among the surviving eight patients, none developed COVID-19 infection during follow-up period. There was no significant difference in outcome parameters when compared to patients who received hearts from donors who tested negative for COVID-19 during the same time period at our center. CONCLUSION: Keeping in mind the significant waitlist mortality in patients awaiting heart transplantation, COVID-19-positive donors should be considered for heart transplantation to help expand the donor pool and potentially reduce waitlist mortality.

Palliative Inotropes in Advanced Heart Failure: Comparing Outcomes Between Milrinone and Dobutamine.

BACKGROUND: We sought to describe and compare outcomes among advanced patients with heart failure (not candidates for orthotopic heart transplant/left ventricular assist device) on long-term milrinone or dobutamine, which are not well-studied in the contemporary era. METHODS AND RESULTS: We included adults with refractory stage D heart failure who were not candidates for orthotopic heart transplant or left ventricular assist device and discharged on palliative dobutamine or milrinone. The primary outcome was 1-year survival. A 6-month predictor of survival analysis was conducted. A total of 248 patients (133 on milrinone, 115 on dobutamine) were included. There were no differences in baseline comorbidities between milrinone and dobutamine cohorts, except for the prevalence of chronic kidney disease, which was higher in the dobutamine group. On discharge, the proportion of patients on beta-blockers and mineralocorticoid antagonists was higher in milrinone group. Overall, the 1-year mortality rate was 70%. The dobutamine cohort had a significantly higher 1-year mortality rate (84% vs 58%, P <0.001). The type of inotrope did not predict survival at 6 months when adjusted for discharge medications and comorbidities. Beta-blockers and angiotensin-converting enzyme/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor continued at discharge predicted survival at 6 months. CONCLUSIONS: The 1-year mortality from palliative inotropes remains high. Compared with dobutamine, use of milrinone was associated with improved survival owing to better optimization of guideline-directed medical therapy, primarily beta-blocker therapy.

Maternal Stressful Life Events During the Periconceptional Period and Orofacial Clefts: A Systematic Review and Meta-Analysis.

OBJECTIVE: To assess whether women who experience stressful life events during the periconceptional period are at higher risk of giving birth to a baby with an orofacial cleft (OFC). DESIGN: Systematic review and meta-analysis of studies reporting the proportion of babies born with OFC to mothers exposed and unexposed to population-level or personal-level stressful life events during the periconceptional period. Six electronic databases were searched from inception to August 2020. Risk of bias was assessed using the Newcastle-Ottawa scale. Odds ratios (ORs) for the odds of OFC in babies of exposed mothers relative to unexposed controls were extracted and/or calculated. Random effects meta-analysis was undertaken, stratified by cleft subtype. RESULTS: Of 12 eligible studies, 8 examined experience of personal events and 4 examined population-level events. Studies demonstrated low-moderate risk of bias and there was indication of publication bias. There was some evidence that personal stressful life events were associated with greater odds of cleft lip and/or palate (six studies, OR 1.63, 95% confidence interval (CI) 1.16, 2.30, P = 0.001) and cleft palate only (six studies, OR 1.45, 95% CI 1.02, 2.06, P = 0.04). Population-level events were associated with higher odds of OFC in studies that did not specify subtype (three studies, OR 1.64, 95% CI 1.19, 2.25, P = 0.002), but subtype stratified analyses were underpowered. Heterogeneity was high. CONCLUSIONS: Limited evidence indicated a weak positive association between maternal stressful life events during the periconceptional period and risk of OFC in the offspring, but further studies with greater consistency in research design are needed.

Ongoing controversies and recent insights of the ARMS2-HTRA1 locus in age-related macular degeneration.

Age-related macular degeneration (AMD) is the most common cause of central vision loss among elderly populations in industrialized countries. Genome-wide association studies have consistently associated two genomic loci with progression to late-stage AMD: the complement factor H (CFH) locus on chromosome 1q31 and the age-related maculopathy susceptibility 2-HtrA serine peptidase 1 (ARMS2-HTRA1) locus on chromosome 10q26. While the CFH risk variant has been shown to alter complement activity, the ARMS2-HTRA1 risk haplotype remains enigmatic due to high linkage disequilibrium and inconsistent functional findings spanning two genes that are plausibly causative for AMD risk. In this review, we detail the genetic and functional evidence used to support either ARMS2 or HTRA1 as the causal gene for AMD risk, emphasizing both the historical development and the current understanding of the ARMS2-HTRA1 locus in AMD pathogenesis. We conclude by summarizing the evidence in favor of HTRA1 and present our hypothesis whereby HTRA1-derived ECM fragments mediate AMD pathogenesis.

The Xist lncRNA interacts directly with SHARP to silence transcription through HDAC3.

Many long non-coding RNAs (lncRNAs) affect gene expression, but the mechanisms by which they act are still largely unknown. One of the best-studied lncRNAs is Xist, which is required for transcriptional silencing of one X chromosome during development in female mammals. Despite extensive efforts to define the mechanism of Xist-mediated transcriptional silencing, we still do not know any proteins required for this role. The main challenge is that there are currently no methods to comprehensively define the proteins that directly interact with a lncRNA in the cell. Here we develop a method to purify a lncRNA from cells and identify proteins interacting with it directly using quantitative mass spectrometry. We identify ten proteins that specifically associate with Xist, three of these proteins--SHARP, SAF-A and LBR--are required for Xist-mediated transcriptional silencing. We show that SHARP, which interacts with the SMRT co-repressor that activates HDAC3, is not only essential for silencing, but is also required for the exclusion of RNA polymerase II (Pol II) from the inactive X. Both SMRT and HDAC3 are also required for silencing and Pol II exclusion. In addition to silencing transcription, SHARP and HDAC3 are required for Xist-mediated recruitment of the polycomb repressive complex 2 (PRC2) across the X chromosome. Our results suggest that Xist silences transcription by directly interacting with SHARP, recruiting SMRT, activating HDAC3, and deacetylating histones to exclude Pol II across the X chromosome.

Clinical and genetic determinants of ovarian metastases from colorectal cancer.

BACKGROUND: Ovarian metastases from colorectal cancer (OM-CRC) often are unresponsive to chemotherapy and are associated with poor survival. To the authors' knowledge, the clinicopathologic and genomic predictors of OM-CRC are poorly characterized and optimal clinical management remains unclear. METHODS: Women with a histopathological diagnosis of OM-CRC who were treated at Memorial Sloan Kettering Cancer Center from 1999 to 2015 were identified. Next-generation somatic mutation profiling (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT]) was performed on 38 OM-CRC cases, including 21 matched tumor pairs/trios. Regression models were used to analyze variables associated with progression-free survival and overall survival (OS). RESULTS: Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), SMAD family member 4 (SMAD4), and neurotrophic receptor tyrosine kinase 1 (NTRK1) mutations were more frequent in cases of OM-CRC than in instances of CRC occurring without OM. SMAD4 and lysine methyltransferase 2D (KMT2D) mutations were associated with reduced OS. Matched multisite tumor sequencing did not identify OM-specific genomic alterations. Of the 195 patients who underwent oophorectomy for OM-CRC (median age, 49 years with a progression-free survival of 9.4 months and an OS of 23 months from oophorectomy), 76% had extraovarian metastasis (EOM). In multivariable analysis, residual disease after surgery (R2 resection) was associated with worse survival. Patients with EOM were less likely to achieve R0/R1 surgical resection status (complete macroscopic resection without clinical/radiological evidence of disease) (48% vs 94%). However, if R0/R1 resection status was achieved, both patients with (35.9 months vs 12 months) and without (43.2 months vs 14.5 months) EOM were found to have better OS. Among 114 patients with R0/R1 resection status, 23 (20%) had no disease recurrence, including 10 patients (9%) with > 3 years of follow-up. CONCLUSIONS: Loss-of-function alterations in SMAD4 are frequent and predictive of worse survival in patients with OM-CRC. Similar to oligometastatic CRC to the lung or liver, surgical resection of OM-CRC is associated with a better outcome only if all macroscopic metastatic disease is resected. Cancer 2017;123:1134-1143. © 2016 American Cancer Society.

Educational and Psychosocial Support Needs in Lynch Syndrome: Implementation and Assessment of an Educational Workshop and Support Group.

Few reports of educational and counseling support resources exist for Lynch syndrome (LS), a disorder requiring multi-organ cancer screening and specialized medical care throughout adult life. Here we describe the development and efficacy of two resources designed to address this need, the Memorial Sloan Kettering Cancer Center Clinical Genetics Service annual Lynch Syndrome Educational Workshop (LSEW), and a quarterly Lynch Syndrome Patient Advocacy Network (LSPAN) support group. The LSEW and LSPAN were implemented beginning in 2012. Participant survey data evaluating satisfaction, clarity, and unmet needs for each event were retrospectively analyzed and summarized using descriptive statistics. Annual LSEW attendance ranged from 53 to 75 total participants. LSEW year 1 participants indicated a need for a support group, and preferred in-person meetings at a frequency of every 3-6 months. For LSEW year 2-5 participants, >96 % reported satisfaction with the LSEW, and >82 % expressed interest in secure online support. Common themes for improvement included increased time for question and answer sessions and additional introductory genetics education. Responding LSPAN participants (n = 57 total survey responses in 11 meetings) found the meetings helpful (100 %), information clear (91 %), and presence of a genetic counselor useful (67 %). Desired discussion topics included coping with stress and anxiety, development of a support network, family communication about LS, genetic testing decisions, and bereavement. Following genetic counseling, a need exists for ongoing educational and emotional support in LS. Implementation of resources such as the LSEW and LSPAN is feasible and perceived as helpful by participants.

Developmental uterovaginal anomalies and histologic findings in transgender patients receiving gender-affirming hysterectomies: A large case series.

OBJECTIVE: To describe the incidence of uterovaginal anomalies and histologic findings in transgender and nonbinary (TGNB) patients seeking hysterectomies. METHODS: All patients receiving gender-affirming hysterectomies between 2013 and 2023 were retrospectively reviewed. Primary outcomes included uterovaginal anomalies and histological findings. Multivariable logistic regressions were performed to evaluate relationships between variables of interest and whether they predict findings of uterovaginal anomalies, inactive endometrium, adenomyosis, leiomyoma, endometriosis, and cervical atrophy. RESULTS: 278 patients received hysterectomies at an average age of 29.2 ± 8.3 years. Seven patients (2.5%) were found to have a developmental anomaly, including two bicornuate uterus (0.7%), two unicornuate uterus (0.7%), one septate uterus (0.4%), and two vaginal septum (0.7%). 60 patients (21.6%) were found to have inactive endometrium and 26 patients (9.4%) had cervical atrophy. Although 262 patients (94.2%) were on testosterone therapy, hormone duration was not a significant predictor of any uterine findings. CONCLUSION: This study describes uterovaginal anomalies in a large cohort of patients receiving gender-affirming hysterectomies. Although long-term testosterone use is commonly believed to be associated with endometrial and cervical atrophy, this study shows no such association.

Mutant strains of Pichia pastoris with enhanced secretion of recombinant proteins.

Although Pichia pastoris is a popular protein expression system, it exhibits limitations in its ability to secrete heterologous proteins. Therefore, a REMI (restriction enzyme mediated insertion) strategy was utilized to select mutant beta-g alactosidase s upersecretion (bgs) strains that secreted increased levels of a ß-galactosidase reporter. Many of the twelve BGS genes may have functions in intracellular signaling or vesicle transport. Several of these strains also appeared to contain a more permeable cell wall. Preliminary characterization of four bgs mutants showed that they differed in the ability to enhance the export of other reporter proteins. bgs13, which has a disruption in a gene homologous to Saccharomyces cerevisiae protein kinase C (PKC1), gave enhanced secretion of most recombinant proteins that were tested, raising the possibility that it has the universal super-secreter phenotype needed in an industrial production strain of P. pastoris.

The Efficacy of Liposomal Bupivacaine in Regional Nerve Blocks for Below Knee Amputations.

Postamputation pain is highly prevalent. Opioids are often utilized postoperatively; however, they have significant side effects. Liposomal bupivacaine (LB) was introduced to extend nerve blocks from hours into days. Regional nerve blocks with LB for below knee amputation (BKA) is a novel approach which may reduce opioid use after surgery. A retrospective review was conducted for patients who had received LB nerve blocks compared to none for postoperative pain control in BKAs. Daily average opioid consumption was evaluated from the time in postoperative acute care unit until day of discharge in oral morphine equivalents (OME). 69 patients who underwent below knee amputations were reviewed. The mean average daily OME was lower in the LB group compared to control group(25.0 vs 50.5 OME, respectively; P = .002) A higher percentage of patients in the study group were categorized in the minimal opioid use when compared to the control group LB regional nerve blocks for the BKA population are considered a novel approach in pain control. Our exploratory study shows that patients who received LB nerve blocks may have decreased opioid consumption after surgery.

Relationships between diversity demographics, psychological distress, and suicidal thinking in the veterinary profession: a nationwide cross-sectional study during COVID-19.

Purpose: This study aimed to determine the relationship between demographic diversity and veterinary professionals regarding their psychological distress and suicidal experiences. This study also aimed to determine what demographic factors were associated with psychological distress and suicidal experiences for veterinary professionals. Methods: This study used a cross-sectional web-based questionnaire to assess the prevalence of diversity, psychological distress, and suicidality in individuals over 18 working in the veterinary field within the United States. The study received 2,482 responses resulting in 2,208 responses that were included in the analysis. Descriptive statistics were performed to identify the categories with the highest rates of psychological distress, suicidal thoughts, and suicidal behaviors. Binomial logistic regressions were conducted to identify the strongest statistical predictors of psychological distress (Kessler-6-K6), suicidal thinking and suicide behaviors. Results: Of the 2,208 respondents included in the analysis, 888 (41%) were experiencing serious psychological distress and 381 (17.3%) had considered suicide in the past 12 months. Results of the binomial regressions indicate gender, social class, age, and disability status were the strongest predictors of psychological distress. When controlling for psychological distress, the strongest predictors of suicidal thinking were sexual orientation, marital status, and professional role. Implications: Limited research has been done to explore the relationship between demographic diversity of veterinary professionals and psychological distress, suicidal thoughts, and suicidal behaviors specifically. These results shed light on multiple demographic factors that promote and attenuate mental health, as well as the importance of asking respondents their demographic identities in veterinary medicine research. This research attempts to identify these mental health factors without collapsing categories with small sample sizes, which does cause a limitation in statistical power, yet also demonstrates how to increase inclusivity in research.

A survey of dental services in England providing targeted care for people experiencing social exclusion: mapping and dimensions of access.

Introduction Poor oral health and barriers to accessing dental services are common among people experiencing social exclusion. This population experience a disproportionate and inequitable burden of oral disease. A small number of dental services have published models of care that target this population, but no national surveys have been conducted.Aims This study aims to identify what types of services are providing dental and oral healthcare for people experiencing social exclusion in England and the models of delivery adopted by these services.Methods A snowballing sampling strategy was used to identify services that provide targeted for adults experiencing social exclusion. The study used a survey to collect data about the location, service models and barriers and enablers of these services.Results In total, 74 responses from different services met the inclusion criteria for the study. Seventy one were included in the mapping exercise and 53 provided free-text comments that contributed to an understanding of barriers and enablers of services.Discussion Most services operated to meet the needs of the mainstream population and described inflexibilities in their service design models as barriers to providing care for socially excluded groups.Conclusion Limitations of current models of service delivery create frustrations for providers and people experiencing social exclusion. Creative commissioning and organisational flexibility are key to facilitating adaptable services.

The interplay of oxidative stress and ARMS2-HTRA1 genetic risk in neovascular AMD.

Age-related macular degeneration (AMD) is the leading cause of vision loss in adults over 60 years old globally. There are two forms of advanced AMD: "dry" and "wet". Dry AMD is characterized by geographic atrophy of the retinal pigment epithelium and overlying photoreceptors in the macular region; whereas wet AMD is characterized by vascular penetrance from the choroid into the retina, known as choroidal neovascularization (CNV). Both phenotypes eventually lead to loss of central vision. The pathogenesis of AMD involves the interplay of genetic polymorphisms and environmental risk factors, many of which elevate retinal oxidative stress. Excess reactive oxygen species react with cellular macromolecules, forming oxidation-modified byproducts that elicit chronic inflammation and promote CNV. Additionally, genome-wide association studies have identified several genetic variants in the age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1 (ARMS2-HTRA1) locus associated with the progression of late-stage AMD, especially the wet subtype. In this review, we will focus on the interplay of oxidative stress and HTRA1 in drusen deposition, chronic inflammation, and chronic angiogenesis. We aim to present a multifactorial model of wet AMD progression, supporting HTRA1 as a novel therapeutic target upstream of vascular endothelial growth factor (VEGF), the conventional target in AMD therapeutics. By inhibiting HTRA1's proteolytic activity, we can reduce pro-angiogenic signaling and prevent proteolytic breakdown of the blood-retina barrier. The anti-HTRA1 approach offers a promising alternative treatment option to wet AMD, complementary to anti-VEGF therapy.

Use of patient-reported controls for secular trends to study disparities in cancer-related job loss.

PURPOSE: Racial/ethnic minorities experience greater job loss than whites during periods of economic downturn and after a cancer diagnosis. Therefore, race/ethnicity-matched controls are needed to distinguish the impact of illness on job loss from secular trends METHODS: Surveys were administered during and 4-month post-completion of breast cancer treatment. Patients were pre-diagnosis employed women aged 18-64, undergoing treatment for stage I-III breast cancers, who spoke English, Chinese, Korean, or Spanish. Each patient was asked to: (1) nominate peers who were surveyed in a corresponding timeframe (active controls), (2) report a friend's work status at baseline and follow-up (passive controls). Both types of controls were healthy, employed at baseline, and shared the nominating patient's race/ethnicity, language, and age. The primary outcome was number of evaluable patient-control pairs by type of control. A patient-control pair was evaluable if work status at follow-up was reported for both individuals. RESULTS: Of the 180 patients, 25% had evaluable active controls (45 patient-control pairs); 84% had evaluable passive controls (151 patient-control pairs). Although patients with controls differed from those without controls under each strategy, there was no difference in the percentage of controls who were working at follow-up (96% of active controls; 91% of passive controls). However, only 65% of patients were working at follow-up. CONCLUSIONS: The majority of patients had evaluable passive controls. There was no significant difference in outcome between controls ascertained through either method IMPLICATIONS FOR CANCER SURVIVORS: Passive controls are a low-cost, higher-yield option to control for secular trends in racially/ethnically diverse samples.

Temporary intravascular shunts after civilian arterial injury: A prospective multicenter Eastern Association for the Surgery of Trauma study.

INTRODUCTION: We sought to determine the impact of the indication for shunt placement on shunt-related outcomes after major arterial injuries. We hypothesized that a shunt placed for damage control indications would be associated with an increase in shunt-related complications including shunt dislodgement, thrombosis, or distal ischemia. PATIENTS & METHODS: A prospective, multicenter study (eleven level one US trauma centers) of all adult trauma patients undergoing temporary intravascular shunts (TIVS) after arterial injury was undertaken (January 2017-May 2019). Exclusion criteria included age <15years, shunt placement distal to popliteal/brachial arteries, isolated venous shunts, and death before shunt removal. Clinical variables were compared by indication and shunt-related complications. The primary endpoint was TIVS complications (thrombosis, migration, distal ischemia). RESULTS: The 66 patients who underwent TIVS were primarily young (30years [IQR 22-36]) men (85%), severely injured (ISS 17 [10-25]) by penetrating mechanisms (59%), and had their shunts placed for damage control (41%). After a median SDT of 198min [89-622], 9% experienced shunt-related complications. Compared by shunt placement indication (damage control shunts [n=27] compared to non-damage control shunts [n=39]), there were no differences in gender, mechanism, extremity AIS, MESS score, fractures, or surgeon specialty between the two groups (all p>0.05). Patients with shunts placed for damage control indications had more severe injuries (ISS 23.5 compared to 13; SBP 100 compared to 129; GCS 11 compared to 15; lactate 11.5 compared to 3.6; all p<0.05), and had more frequent shunt complication predictors, but damage control shunts did not have significantly more TIVS complications (11.1% compared to 7.7%, p=0.658). Shunt complication patients were discharged home less often (33% vs 65%; p<0.05) but all survived. CONCLUSION: Shunts placed for damage control indications were not associated with shunt complications in this prospective, multicenter study.

Structure of the Mucosal and Stool Microbiome in Lynch Syndrome.

The gut microbiota has been associated with colorectal cancer (CRC), but causal alterations preceding CRC have not been elucidated. To prospectively assess microbiome changes prior to colorectal neoplasia, we investigated samples from 100 Lynch syndrome patients using 16S rRNA gene sequencing of colon biopsies, coupled with metagenomic and metatranscriptomic sequencing of feces. Colectomy and CRC history represented the largest effects on microbiome profiles. A subset of Clostridiaceae were depleted in stool corresponding with baseline adenomas, while Desulfovibrio was enriched both in stool and in mucosal biopsies. A classifier leveraging stool metatranscriptomes resulted in modest power to predict interval development of preneoplastic colonic adenoma. Predictive transcripts corresponded with a shift in flagellin contributors and oxidative metabolic microenvironment, potentially factors in local CRC pathogenesis. This suggests that the effectiveness of prospective microbiome monitoring for adenomas may be limited but supports the potential causality of these consistent, early microbial changes in colonic neoplasia.

Mismatch Repair-Deficient Rectal Cancer and Resistance to Neoadjuvant Chemotherapy.

PURPOSE: Evaluate response of mismatch repair-deficient (dMMR) rectal cancer to neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: dMMR rectal tumors at Memorial Sloan Kettering Cancer Center (New York, NY) were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty patients with dMMR rectal cancer were identified by IHC and/or microsatellite instability analysis, with initial treatment response compared with a matched MMR-proficient (pMMR) rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity. RESULTS: Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), six (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors (P = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable with 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome with enrichment of germline MSH2 and MSH6 mutations when compared with 193 patients with Lynch syndrome-associated colon cancer (MSH2, 57% vs 36%; MSH6, 17% vs 9%; P < 0.003). CONCLUSIONS: Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for Lynch syndrome in patients with dMMR rectal cancer.

WormBot, an open-source robotics platform for survival and behavior analysis in C. elegans.

Caenorhabditis elegans is a popular organism for aging research owing to its highly conserved molecular pathways, short lifespan, small size, and extensive genetic and reverse genetic resources. Here we describe the WormBot, an open-source robotic image capture platform capable of conducting 144 parallel C. elegans survival and behavioral phenotyping experiments. The WormBot uses standard 12-well tissue culture plates suitable for solid agar media and is built from commercially available robotics hardware. The WormBot is controlled by a web-based interface allowing control and monitoring of experiments from any internet connected device. The standard WormBot hardware features the ability to take both time-lapse bright field images and real-time video micrographs, allowing investigators to measure lifespan, as well as heathspan metrics as worms age. The open-source nature of the hardware and software will allow for users to extend the platform and implement new software and hardware features. This extensibility, coupled with the low cost and simplicity of the system, allows the automation of C. elegans survival analysis even in small laboratory settings with modest budgets.