Citations

Abstract The phosphorylation of histone H2A.X into γH2A.X is a crucial early event in the DNA damage response, marking DNA damage sites and initiating repair processes. While ATM kinase is traditionally recognized as the primary mediator of H2A.X phosphorylation, our study identifies serine/threonine kinase 39 (STK39) as a novel enhancer of this critical signaling pathway. We demonstrate that after DNA damage, STK39 undergoes phosphorylation by the ATM kinase, facilitating its interaction with the Mre11-Rad50-Nbs1 complex and subsequent recruitment to chromatin. This recruitment enables STK39 to further phosphorylate H2A.X, thus amplifying γH2A.X production and promoting homologous recombination repair. Notably, we observe a significant upregulation of STK39 in pancreatic adenocarcinoma (PAAD) tissues, correlating with heightened resistance to PARPi therapy. Furthermore, we demonstrate the synergistic efficacy of combining STK39 inhibition with PARP inhibitors in suppressing and reversing PAAD growth. This study not only provides new insights into the molecular dynamics of H2A.X phosphorylation but also highlights the therapeutic potential of targeting STK39 to enhance PARPi sensitivity in PAAD (created with BioRender).

ABSTRACTBackgroundThere is a known association between common variable immunodeficiency (CVID) and granulomas in multiple organ systems, including the skin, lung, liver, and spleen. Rubella virus has also been detected within cutaneous granulomas in both immunocompetent and immunocompromised hosts. We present a retrospective case series of patients with CVID and granulomatous skin disease and describe the spectrum of clinical and histopathologic features, including the status of rubella virus in the cutaneous granulomas.MethodsWe retrospectively reviewed the clinical and histopathological characteristics of patients diagnosed with CVID at our institution, with cutaneous findings and skin biopsies available for review between 1990 and 2023, demonstrating granulomatous inflammation.ResultsEight patients met the inclusion criteria. The most common histopathologic pattern was palisaded granulomatous inflammation, seen in five of eight cases. Three cases showed strictly sarcoidal granulomas. Background inflammation was peri‐granulomatous (8/8) and the predominant background inflammatory cell type was lymphocytic (6/8). Rubella virus testing was performed for seven of eight cases and found to be positive in one case.ConclusionCutaneous granulomatous disease in CVID can present with a spectrum of clinical morphologies, granulomatous patterns, and variable rubella virus persistence. Dermatopathologists should be aware of the spectrum of findings when considering cutaneous CVID–related granulomatous disease in the differential diagnosis.

Background and Objective: Weight loss and small intestinal bacterial overgrowth (SIBO) are common in Parkinson’s disease (PD). We aimed to study the relationship between weight loss and SIBO in PD. Methods: This was a cross-sectional study with a prospective, interventional component. Consecutive patients seen in the PD clinic who agreed to participate underwent extensive history, movement exam, SIBO breath testing and answered questionnaires. A subset of those in the weight loss group were treated with rifaximin for 14 days and returned 3 months later for an assessment of their weight, GI symptoms, quality of life and SIBO status. All analyses were adjusted for age and disease duration. Results: Fifty-one patients participated in the study; 37 without weight loss and 14 with weight loss. Total energy intake including the distribution of macronutrient intake was similar between groups while physical activity was less in those with weight loss. PD severity scores did not differ between groups; however, PD-specific quality of life scores were significantly worse for the summary index and the subscales of emotional well-being, social support and communication. The prevalence of constipation, dyspepsia and abdominal pain/discomfort was higher in those with weight loss. The prevalence of SIBO was 14% in the weight loss group and was not different between groups. Eight PD patients with weight loss were treated with rifaximin; no significant change in GI symptoms, quality of life or weight was seen 3 months later. Conclusion: Although a number of differences were identified in quality of life and gastrointestinal symptoms between groups with and without weight loss, SIBO was not associated with weight loss in patients with PD. Given the exploratory nature and small number of patients with weight loss, however, further study is suggested.

Recent literature has emphasized the role of hand surgeons in screening patients with carpal tunnel syndrome (CTS) for amyloidosis by performing a carpal tunnel synovial biopsy during open carpal tunnel release (CTR). This has led to misconceptions about the diagnostic utility of synovial biopsy and the clinical evaluation of suspected amyloidosis. Controversy over carpal tunnel biopsy is exacerbated by minimally invasive advances in CTR procedures. This current perspective aims to determine the role of carpal tunnel synovial biopsy in amyloidosis and provide an update for hand surgeons regarding the nuances of amyloidosis. We conclude that carpal tunnel synovial biopsy should not be performed without CTS symptoms but only in patients meeting criteria for open CTR such as in those with severe symptoms which have failed nonoperative treatment and minimally invasive procedures are contraindicated. A screening approach for amyloidosis is proposed in patients presenting with CTS symptoms. Despite advances in the understanding, treatment, and diagnosis of amyloidosis, there remains a need for accurate, specific, and sensitive diagnostic tests.

Background: The treatment for Kienböck disease varies widely based on the status of the lunate. To date, there is no consensus regarding the optimal treatment for patients with coronal plane fractures of the lunate, or Lichtman Stage IIIC. Therefore, the purpose of this study was to assess whether coronal plane fractures of the lunate in Kienböck disease healed after surgical intervention, and to determine the outcomes after surgical fixation of the lunate compared with treatment with salvage procedures. Methods: A retrospective review of 36 patients with Lichtman IIIC Kienböck disease was conducted. Patients were classified into lunate reconstruction (vascularized bone graft [VBG] or non-VBG) or salvage procedures (proximal row carpectomy [PRC] or limited fusion). Preoperative and postoperative visual analog scale (VAS) pain, range of motion, grip strength, and Mayo Wrist Score (MWS) were analyzed. Radiographs and computed tomographic scans were reviewed for Lichtman stage, fracture location, union, modified carpal height ratio, Stahl index, and radioscaphoid angle. Results: Thirteen patients underwent lunate reconstruction, 13 underwent limited fusion, and 10 underwent PRC. The overall union rate was 45% after lunate reconstruction, with average time to union of 7 months. There were no differences in union rates between VBG and non-VBG. All 3 groups experienced improvement in their postoperative grip strength and MWS. There were no statistically significant differences in preoperative to postoperative changes in clinical outcome measures between the 3 cohorts; however, when we compared lunate reconstruction with all patients who underwent salvage procedures (limited carpal fusion and PRC), we noted the latter had improved functional outcomes ( P = .019). Four patients (31%) in the reconstruction cohort and 2 patients (8%) in the limited carpal fusion group required reoperation at latest follow-up. Conclusions: Union rate of coronal plane fractures in Kienböck disease remains variable. While the proportion of patients requiring reoperation was higher in the reconstruction group, all groups of patients experienced improvement in their clinical outcomes, without a significant difference between cohorts.

SummaryBackgroundVarying obesogenic inherited predisposition in early to later life may differentially impact colorectal cancer (CRC) development. Previous Mendelian randomization (MR) studies, conducted in populations of European genetic similarity, have not observed any significant associations between early life body weight with CRC risk. However, it remains unclear whether body mass index (BMI) at different early lifetime points is causally related with CRC risk in both Europeans and East Asian populations.ObjectivesWe conducted a two‐sample MR study to investigate potential causal relationships between genetically predicted BMI during early life (birth to 8 years old) and at specific periods (birth, transient, early rise and late rise) and CRC risk.MethodsSummary data were obtained from genome‐wide association study (GWAS) of BMI in 28 681 children from the Norwegian Mother, Father and Child Cohort Study (MoBa) study and applied to CRC GWAS data from European and East Asian descent populations (102 893 cases and 485 083 non‐cases).ResultsThere were no significant associations observed between early life BMI and CRC risk in European or East Asian populations. The effect estimates were similar in European studies (odds ratio [OR] per a 1‐standard deviation [SD] increase: 1.01, 95% confidence interval [CI]: 0.95, 1.07) and in East Asians (OR per a 1‐SD increase: 1.02, 95% CI: 0.91, 1.14). Similar nonsignificant associations were found between time of BMI measurement during childhood and cancer‐site‐specific analyses.ConclusionsWe found little evidence of any associations between early life adiposity on later life CRC risk.

Objective Identify sociodemographic factors and comorbidities predictive of nasoalveolar molding (NAM) treatment completion and noncompletion in infants with cleft lip with or without (+/–) cleft palate in a rural-suburban population. Design Retrospective cohort study. Setting Tertiary medical center. Patients, Participants Infants diagnosed with cleft lip +/- cleft palate who initiated NAM treatment between 2013 and 2023. Forty-seven patients met inclusion criteria. Main Outcome Measure(s) Prevalence of NAM treatment completion, defined as continued attendance of NAM appointments until initial lip repair surgery. Results NAM treatment noncompletion rate of 23.4%. Noncomplete NAM treatment was associated with greater additional unscheduled NAM visits ( P < .001); increased days inpatient after birth ( P < .001); NICU admission ( P < .001); public insurance ( P = .007); preterm birth ( P = .008); history of social work visits ( P = .024); increased comorbidities ( P = .028); non-Caucasian race ( P = .034); and presence of siblings ( P = .036). Associated comorbidities included use of feeding tube ( P < .001); and conditions related with renal ( P < .001); cardiac ( P = .004); failure to thrive ( P = .009); syndromes ( P = .009); orthopedic ( P = .011); pulmonary ( P = .022); and ophthalmologic systems ( P = .041). Conclusions Increased overall health complexity, public insurance status, and need for social work support were identified as factors associated with NAM noncompletion. These variables can help identify patients at risk of noncompletion and empower providers to supply individualized support and resources.