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Objective: The aim of this study was to investigate the mechanism of acupotomology (Apo) in the prevention of articular cartilage destruction via the promotion of chondrocyte proliferation and chondrocyte expression of cell cycle regulators, CyclinD1, CDK4 and CDK6 in a rabbit knee osteoarthritis (KOA) model. Methods: Twenty-eight rabbits were randomly divided into a control group, an OA (osteoarthritis) model group, an Apo (acupotomology) group and EA (electro-acupuncture) group (n = 7). Improved Videman's method was used to induce a rabbit model of KOA over 6 weeks. One week later, acupotomy and electro-acupuncture therapy was applied to animals in the respective groups and treatment lasted 4 weeks. Following these treatments, quantitative real-time PCR, immunohistochemical staining and western blotting were performed to assess the mRNA and protein levels of cell cycle regulators CyclinD1 (Cell cycle protein D1), CDK4 (Cyclin-dependent kinase 4) and CDK6 (Cyclin-dependent kinase 6). Ethology measures and knee morphology were also compared among groups. Results: The Lequesne MG index score of morphology was increased (P .05). Compared with the EA group, the morphology score was decreased in Apo group (P

High early age concrete temperatures can lead to many problems such as an increased rate of cement hydration, as well as an increased rate of moisture loss from fresh concrete which can ultimately lead to the occurrence of plastic shrinkage cracking. Concrete is also batched and cast at various ambient temperatures which greatly influences the temperature development of the concrete after placement. There is a need to understand the influence of concrete temperature on the plastic cracking of concrete. This study investigated the temperature development over the thickness of a concrete slab when exposed to different initial concrete and ambient temperatures as well as the effect these factors have on plastic shrinkage cracking. This was achieved by experiments on concrete samples at varying temperatures while measuring the concrete temperature, pore water evaporation, shrinkage, settlement, setting times and plastic shrinkage cracking magnitude. These tests were conducted in a climate controlled chamber. It was concluded that exposure to higher initial concrete and ambient temperatures significantly increases the average temperature over the thickness of the concrete. The evaporation of pore water was higher when exposed to higher evaporation conditions. The plastic shrinkage, settlement and plastic shrinkage cracking were more severe in the presence of higher initial concrete and ambient temperatures even though the critical period and setting times were reduced due to an increase in the concrete temperature. Finally, the surface temperature of the concrete as tested in slabs up to 100 mm in thickness can be used as a good indication of the temperature development in the lower layers of the concrete.

The cracking of fresh concrete, while still in a plastic state, includes both plastic settlement and plastic shrinkage cracking, which starts once the concrete is cast to around the final setting time. The cracking process is complex and is influenced by numerous factors which include the climate, mix proportions, element geometry and construction procedures. Preventing these cracks therefore remains a problem in practice. One of the reasons for this is the lack of a model that can be used to determine the location, timing and severity of the cracking before the cracking occurs. The main challenges with such a model are the testing of the fresh concrete to determine the tensile material properties, the appropriate constitutive law needed, and the time dependency of material properties as well as the anisotropic volume change. This paper presents a finite element model that uses a total strain smeared cracking approach and accounts for both the time dependency of material properties and the anisotropic volume change. The model gives an adequate representation of the cracking behaviour of fresh concrete for extreme climates but not for normal to moderate climates, mainly due to the size discrepancy between the interior and surface cracks during experiments as well as the relaxation of stresses that are not accounted for in the model. A parameter study showed that both the settlement and shrinkage strains significantly influence and therefore govern the size of the final plastic crack, while the material mechanical properties only influence the time of crack onset and rate of crack widening.

During the plastic state of concrete, any hindrance or resistance of the free volume change in plastic concrete induce tensile stresses and or strains in the concrete element. Crack formation is expected to occur if the tensile stress and strain is greater than the capacity of the concrete. Investigation into the tensile properties and relaxation behaviour of plastic concrete was carried out using a direct tensile testing machine. The capillary pressure was measured during the tensile tests in low evaporation conditions, as well as in a climate controlled chamber where the concrete was exposed to high evaporation conditions. Most of the measured strength gain (tensile capacity) of the concrete is due to the capillary pressure in the pores of the fresh concrete which keeps the particles together by means of free water in the concrete during the early stiffening phase of the concrete. Later the hydration products bridge the pores which provides strength to the concrete. The capillary pressure results indicate how the rate of hydration influence the interconnectivity of the pores, and the contribution to the measured strength gain of the fresh concrete. The capillary pressure measurements during tensile tests revealed that the mechanism behind relaxation is the negative capillary pressure build-up induced by the mechanical tensile strain. The results also showed a correlation between the build-up of the capillary pressure in the concrete and the tensile deformation of the fresh concrete where the capillary pressure increased as the tensile load increased.

Treatment with analogues of the SERCA-inhibitor Thapsigargin is a promising new approach for a wide variety of cancer entities. However, our previous studies on various tumor cells suggested resistance of SEC62 over-expressing tumors to this treatment. Therefore, we proposed the novel concept that e.g. lung-, prostate-, and thyroid-cancer patients should be tested for SEC62 over-expression, and developed a novel therapeutic strategy for a combinatorial treatment of SEC62 over-expressing tumors. The latter was based on the observations that treatment of SEC62 over-expressing tumor cells with SEC62-targeting siRNAs showed less resistance to Thapsigargin as well as a reduction in migratory potential and that the siRNA effects can be mimicked by the Calmodulin antagonist Trifluoperazine. Therefore, the combinatorial treatment of SEC62 over-expressing tumors was proposed to involve Thapsigargin and Trifluoperazine. Here, we addressed the impact of Thapsigargin and Trifluoperazine in separate and combined treatments of heterotopic tumors, induced by inoculation of human hypopharyngeal squamous cell carcinoma (FaDu)-cells into the mouse flank. Seeding of the tumor cells and/or their growth rate were significantly reduced by all three treatments, suggesting Trifluoperazine is a small molecule to be considered for future therapeutic strategies for patients, suffering from Sec62-overproducing tumors.

BACKGROUND: Hospitals use time-motion studies to monitor process effectiveness and patient waiting. Manual tracking is labor-intensive and potentially influences system performance. New technology known as indoor positioning systems (IPS) may allow automatic monitoring of patient waiting and progress. The authors tested whether an IPS can track patients through a multistep preoperative process. METHODS: The authors used an IPS between October 14, 2005, and June 13, 2006, to track patients in a multistep ambulatory preoperative process: needle localization and excisional biopsy of a breast lesion. The process was distributed across the ambulatory surgery and radiology departments of a large academic hospital. Direct observation of the process was used to develop a workflow template. The authors then developed software to convert the IPS data into usable time-motion data suitable for monitoring process efficiency over time. RESULTS: The authors assigned tags to 306 patients during the study period. Eighty patients never underwent the procedure or never had their tag affixed. One hundred seventy-seven (78%) of the remaining 226 patients successfully matched the workflow template. Process time stamps were automatically extracted from the successful matches, measuring time before radiology (mean +/- SD, 77 +/- 35 min), time in radiology (105 +/- 35 min), and time between radiology and operating room (80 +/- 60 min), which summed to total preoperative time (261 +/- 67 min). CONCLUSIONS: The authors have demonstrated that it is possible to use a combination of IPS technology and sequence alignment pattern matching software to automate the time-motion study of patients in a multidepartment, multistep process with the only day-of-surgery intervention being the application of a tag when the patient arrives. [ABSTRACT FROM AUTHOR]

Abstract Background Coloured-hearing (CH) synesthesia is a perceptual phenomenon in which an acoustic stimulus (the inducer) initiates a concurrent colour perception (the concurrent). Individuals with CH synesthesia "see" colours when hearing tones, words, or music; this specific phenomenon suggesting a close relationship between auditory and visual representations. To date, it is still unknown whether the perception of colours is associated with a modulation of brain functions in the inducing brain area, namely in the auditory-related cortex and associated brain areas. In addition, there is an on-going debate as to whether attention to the inducer is necessarily required for eliciting a visual concurrent, or whether the latter can emerge in a pre-attentive fashion. Results By using the EEG technique in the context of a pre-attentive mismatch negativity (MMN) paradigm, we show that the binding of tones and colours in CH synesthetes is associated with increased MMN amplitudes in response to deviant tones supposed to induce novel concurrent colour perceptions. Most notably, the increased MMN amplitudes we revealed in the CH synesthetes were associated with stronger intracerebral current densities originating from the auditory cortex, parietal cortex, and ventral visual areas. Conclusions The automatic binding of tones and colours in CH synesthetes is accompanied by an early pre-attentive process recruiting the auditory cortex, inferior and superior parietal lobules, as well as ventral occipital areas.

Abstract Background Cell lines represent a key tool in cancer research allowing the generation of neoplasias which resemble initial tumours in in-vivo animal models. The characterisation of early tumour development is of major interest in order to evaluate the efficacy of therapeutic agents. Magnetic resonance imaging (MRI) based in-vivo characterisation allows visualisation and characterisation of tumour development in early stages prior to manual palpation. Contrast agents for MRI such as superparamagnetic iron oxide nanoparticles (SPIOs) and manganese chloride (MnCl2) represent powerful tools for the in-vivo characterisation of early stage tumours. In this experimental study, we labelled prostate cancer cells with MnCl2 or SPIOs in vitro and used 1 T MRI for tracing labelled cells in-vitro and 7 T MRI for tracking in an in-vivo animal model. Methods Labelling of prostate cancer cells CT1258 was established in-vitro with MnCl2 and SPIOs. In-vitro detection of labelled cells in an agar phantom was carried out through 1 T MRI while in-vivo detection was performed using 7 T MRI after subcutaneous (s.c.) injection of labelled cells into NOD-Scid mice (n = 20). The animals were scanned in regular intervals until euthanization. The respective tumour volumes were analysed and corresponding tumour masses were subjected to histologic examination. Results MnCl2in-vitro labelling resulted in no significant metabolic effects on proliferation and cell vitality. In-vitro detection-limit accounted 105 cells for MnCl2 as well as for SPIOs labelling. In-vivo 7 T MRI scans allowed detection of 103 and 104 cells. In-vivo MnCl2 labelled cells were detectable from days 4–16 while SPIO labelling allowed detection until 4 days after s.c. injection. MnCl2 labelled cells were highly tumourigenic in NOD-Scid mice and the tumour volume development was characterised in a time dependent manner. The amount of injected cells correlated with tumour size development and disease progression. Histological analysis of the induced tumour masses demonstrated characteristic morphologies of prostate adenocarcinoma. Conclusions To the best of our knowledge, this is the first study reporting direct in-vitro MnCl2 labelling and 7 T based in-vivo MRI tracing of cancer cells in a model of prostate cancer. MnCl2 labelling was found to be suitable for in-vivo tracing allowing long detection periods. The labelled cells kept their highly tumourigenic potential in-vivo. Tumour volume development was visualised prior to manual palpation allowing tumour characterisation in early stages of the disease.

Abstract Background With the prospect of increasing prevalence of cancer, the issue of multiple primary cancers becomes more relevant. The aim of this study was to estimate the risk of developing a tobacco-related subsequent primary cancer (TRSPC) in persons with a tobacco-related first primary cancer (TRFPC) compared with the general population in Bavaria, Germany. Methods Using data from the Population-Based Cancer Registry Bavaria, we analyzed TRFPC and TRSPC diagnosed in Bavaria between 2002 and 2008 to estimate the relative and absolute risk of developing TRSPC using standardized incidence ratios (SIR) and excess absolute risks (EAR). Results 121,631 TRFPC in men and 75,886 respective cancers in women were registered, which in 2.5% of male and 1.2% of female cancer patients were followed by at least one TRSPC. In both males and females, the highest increased risks compared to the general population were found within the group of cancer in the mouth/pharynx, oesophagus, larynx, and lung/bronchus. Conclusions With respect to cancer in the mouth/pharynx, oesophagus, larynx, lung/bronchus, kidney, urinary bladder and urinary tract, smoking was confirmed as a shared risk factor based on our finding of mutually significantly increased risks of TRSPC. The results of this study illustrate the importance of smoking cessation and of continued follow-up care especially of smokers with the aforementioned TRFPC to detect TRSPC at an early stage.

Abstract Background Phase-contrast magnetic resonance imaging (PC-MRI) enables quantification of cerebrospinal fluid (CSF) flow and total cerebral blood (tCBF) flow and may be of value for the etiological diagnosis of neurodegenerative diseases. This investigation aimed to study CSF flow and intracerebral vascular flow in patients with Alzheimer's disease (AD) and patients with amnesic mild cognitive impairment (a-MCI) and to compare the results with patients with idiopathic normal pressure hydrocephalus (NPH) and with healthy elderly volunteers (HEV). Methods Ten a-MCI and 9 mild AD patients were identified in a comprehensive neurological and neuropsychological assessment. They underwent brain MRI; PC-MRI pulse sequence was performed with the following parameters: two views per segment; flip angle: 25° for vascular flow and 20° for CSF flow; field-of-view (FOV): 14 × 14 mm²; matrix: 256 × 128; slice thickness: 5 mm; with one excitation for exams on the 3 T machine, and 2 excitations for the 1.5 T machine exams. Velocity (encoding) sensitization was set to 80 cm/s for the vessels at the cervical level, 10 or 20 cm/s for the aqueduct and 5 cm/s for the cervical subarachnoid space (SAS). Dynamic flow images were analyzed with in-house processing software. The patients' results were compared with those obtained for HEVs (n = 12), and for NPH patients (n = 13), using multivariate analysis. Results Arterial tCBF and the calculated pulsatility index were significantly greater in a-MCI patients than in HEVs. In contrast, vascular parameters were lower in NPH patients. Cervical CSF flow analysis yielded similar values for all four populations. Aqueductal CSF stroke volumes (in μl per cardiac cycle) were similar in HEVs (34 ± 17) and AD patients (39 ± 18). In contrast, the aqueductal CSF was hyperdynamic in a-MCI patients (73 ± 33) and even more so in NPH patients (167 ± 89). Conclusion Our preliminary data show that a-MCI patients present with high systolic arterial peak flows, which are associated with higher mean total cerebral arterial flows. Aqueductal CSF oscillations are within normal range in AD and higher than normal in NPH. This study provides an original dynamic vision of cerebral neurodegenerative diseases, consistent with the vascular theory for AD, and supporting primary flow disturbances different from those observed in NPH.

Abstract Background Glycemic control and management of dyslipidemia to reduce cardiovascular risk are major therapeutic goals in individuals with type 2 diabetes mellitus (T2DM). This study was performed to evaluate the effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor α/γ (PPARα/γ) agonist, on both lipid and glycemic parameters in obese, hypertriglyceridemic, insulin-resistant rhesus monkeys. Methods A 135-day efficacy study was performed in six rhesus monkeys. After a 28-day baseline assessment (vehicle only), monkeys received oral aleglitazar 0.03 mg/kg per day for 42 days, followed by a 63-day washout period. Plasma levels of markers of glycemic and lipid regulation were measured at baseline, at the end of the dosing period, and at the end of the washout period. Results Compared with baseline values, aleglitazar 0.03 mg/kg per day reduced triglyceride levels by an average of 89% (328 to 36 mg/dL; P = 0.0035 when normalized for baseline levels) and increased high-density lipoprotein cholesterol levels by 125% (46 to 102 mg/dL; P = 0.0007). Furthermore, aleglitazar reduced low-density lipoprotein cholesterol levels (41%) and increased levels of apolipoprotein A-I (17%) and A-II (17%). Aleglitazar also improved insulin sensitivity by 60% (P = 0.001). Mean body weight was reduced by 5.9% from baseline values with aleglitazar at this dose (P = 0.043). Conclusions Aleglitazar, a dual PPARα/γ agonist, has beneficial effects on both lipid and glucose parameters and may have a therapeutic role in modifying cardiovascular risk factors and improving glycemic control in patients with T2DM.

Abstract Background Breast cancer studies frequently focus on the role of the tumor microenvironment in the promotion of cancer; however, the influence of the normal breast microenvironment on cancer cells remains relatively unknown. To investigate the role of the normal breast microenvironment on breast cancer cell tumorigenicity, we examined whether extracellular matrix molecules (ECM) derived from premenopausal African-American (AA) or Caucasian-American (CAU) breast tissue would affect the tumorigenicity of cancer cells in vitro and in vivo. We chose these two populations because of the well documented predisposition of AA women to develop aggressive, highly metastatic breast cancer compared to CAU women. Methods The effects of primary breast fibroblasts on tumorigenicity were analyzed via real-time PCR arrays and mouse xenograft models. Whole breast ECM was isolated, analyzed via zymography, and its effects on breast cancer cell aggressiveness were tested in vitro via soft agar and invasion assays, and in vivo via xenograft models. Breast ECM and hormone metabolites were analyzed via mass spectrometry. Results Mouse mammary glands humanized with premenopausal CAU fibroblasts and injected with primary breast cancer cells developed significantly larger tumors compared to AA humanized glands. Examination of 164 ECM molecules and cytokines from CAU-derived fibroblasts demonstrated a differentially regulated set of ECM proteins and increased cytokine expression. Whole breast ECM was isolated; invasion and soft agar assays demonstrated that estrogen receptor (ER)-, progesterone receptor (PR)/PR- cells were significantly more aggressive when in contact with AA ECM, as were ER+/PR+ cells with CAU ECM. Using zymography, protease activity was comparatively upregulated in CAU ECM. In xenograft models, CAU ECM significantly increased the tumorigenicity of ER+/PR+ cells and enhanced metastases. Mass spectrometry analysis of ECM proteins showed that only 1,759 of approximately 8,000 identified were in common. In the AA dataset, proteins associated with breast cancer were primarily related to tumorigenesis/neoplasia, while CAU unique proteins were involved with growth/metastasis. Using a novel mass spectrometry method, 17 biologically active hormones were measured; estradiol, estriol and 2-methoxyestrone were significantly higher in CAU breast tissue. Conclusions This study details normal premenopausal breast tissue composition, delineates potential mechanisms for breast cancer development, and provides data for further investigation into the role of the microenvironment in cancer disparities.

Abstract Background Golden moles (Chrysochloridae) are small, subterranean, afrotherian mammals from South Africa and neighboring regions. Of the 21 species now recognized, some (e.g., Chrysochloris asiatica, Amblysomus hottentotus) are relatively common, whereas others (e.g., species of Chrysospalax, Cryptochloris, Neamblysomus) are rare and endangered. Here, we use a combined analysis of partial sequences of the nuclear GHR gene and morphological characters to derive a phylogeny of species in the family Chrysochloridae. Results Although not all nodes of the combined analysis have high support values, the overall pattern of relationships obtained from different methods of phylogeny reconstruction allow us to make several recommendations regarding the current taxonomy of golden moles. We elevate Huetia to generic status to include the species leucorhinus and confirm the use of the Linnean binomial Carpitalpa arendsi, which belongs within Amblysominae along with Amblysomus and Neamblysomus. A second group, Chrysochlorinae, includes Chrysochloris, Cryptochloris, Huetia, Eremitalpa, Chrysospalax, and Calcochloris. Bayesian methods make chrysochlorines paraphyletic by placing the root within them, coinciding with root positions favored by a majority of randomly-generated outgroup taxa. Maximum Parsimony (MP) places the root either between chrysochlorines and amblysomines (with Chlorotalpa as sister taxon to amblysomines), or at Chlorotalpa, with the former two groups reconstructed as monophyletic in all optimal MP trees. Conclusions The inclusion of additional genetic loci for this clade is important to confirm our taxonomic results and resolve the chrysochlorid root. Nevertheless, our optimal topologies support a division of chrysochlorids into amblysomines and chrysochlorines, with Chlorotalpa intermediate between the two. Furthermore, evolution of the chrysochlorid malleus exhibits homoplasy. The elongate malleus has evolved just once in the Cryptochloris-Chrysochloris group; other changes in shape have occurred at multiple nodes, regardless of how the root is resolved.

Abstract Background Four nursing mothers consented to anaesthesia for urgent surgery only on condition that their ability to breast feed would not be impaired. Methods Following induction of general anaesthesia with propofol and remifentanil, 65-69% xenon supplemented with remifentanil was used as an inhalational anaesthetic for maintenance. Results After finishing surgery the women could be extubated between 2:52 and 7:22 minutes. The women were fully alert just minutes after extubation and spent about 45 minutes in the recovery room before discharge to a regular ward. They resumed regular breast feeding some time later. The propofol concentration in the blood was measured after 0, 30, 90, and 300 minutes and in the milk after 90 and 300 minutes. Just 90 minutes after extubation, the concentration of propofol in the milk was limited (> 3 mg/l) so that pharmacological effects on the babies were excluded after oral intake. Also, no traces of xenon gas were found in the maternal milk at any time. After propofol induction and maintenance of anaesthesia with xenon in combination with a water-soluble short-acting drug like remifentanil, the concentration of propofol in maternal milk is low (> 3 mg/l 90 min after anesthesia) and harmless after oral intake. Conclusions These results, as well as the rapid elimination and absence of metabolism of xenon, are of great interest to nursing mothers. General anaesthesia with propofol for induction only, combined with remifentanil and xenon for maintenance, has not yet been described in breast feeding mothers.

Abstract Background Little is known about the contribution of transcranial direct current stimulation (tDCS) to the exploration of memory functions. The aim of the present study was to examine the behavioural effects of right or left-hemisphere frontal direct current delivery while committing to memory auditory presented nouns on short-term learning and subsequent long-term retrieval. Methods Twenty subjects, divided into two groups, performed an episodic verbal memory task during anodal, cathodal and sham current application on the right or left dorsolateral prefrontal cortex (DLPFC). Results Our results imply that only cathodal tDCS elicits behavioural effects on verbal memory performance. In particular, left-sided application of cathodal tDCS impaired short-term verbal learning when compared to the baseline. We did not observe tDCS effects on long-term retrieval. Conclusion Our results imply that the left DLPFC is a crucial area involved in short-term verbal learning mechanisms. However, we found further support that direct current delivery with an intensity of 1.5 mA to the DLPFC during short-term learning does not disrupt longer lasting consolidation processes that are mainly known to be related to mesial temporal lobe areas. In the present study, we have shown that the tDCS technique has the potential to modulate short-term verbal learning mechanism.

Abstract Background Radiomicrosphere therapy (RT) utilizing yttrium-90 (90Y) microspheres has been shown to be an effective regional treatment for primary and secondary hepatic malignancies. We sought to determine a large academic institution's experience regarding the extent and frequency of gastrointestinal complications. Methods Between 2004 and 2007, 27 patients underwent RT for primary or secondary hepatic malignancies. Charts were subsequently reviewed to determine the incidence and severity of GI ulceration. Results Three patients presented with gastrointestinal bleeding and underwent upper endoscopy. Review of the pretreatment angiograms showed normal vascular anatomy in one patient, sclerosed hepatic vasculature in a patient who had undergone prior chemoembolization in a second, and an aberrant left hepatic artery in a third. None had undergone prophylactic gastroduodenal artery embolization. Endoscopic findings included erythema, mucosal erosions, and large gastric ulcers. Microspheres were visible on endoscopic biopsy. In two patients, gastric ulcers were persistent at the time of repeat endoscopy 1–4 months later despite proton pump inhibitor therapy. One elderly patient who refused surgical intervention died from recurrent hemorrhage. Conclusion Gastrointestinal ulceration is a known yet rarely reported complication of 90Y microsphere embolization with potentially life-threatening consequences. Once diagnosed, refractory ulcers should be considered for aggressive surgical management.

Abstract Background A platinum doublet is the current standard treatment for good performance status patients with advanced non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (SCLC) with good performance status. However, platinum-based treatment may be associated with significant toxicities, therefore alternative platinum-free combinations should be investigated. Topotecan is a topoisomerase I inhibitor that exerts its cytotoxic effect through stabilization of the topoisomerase I-DNA complex. Preclinical data suggests synergy between topoisomerase I inhibitors and mitotic spindle poisons. Considerable hematologic toxicities have been reported with topotecan dosed for 5 consecutive days in combination with vinorelbine. Therefore, the aim of this study was to evaluate the optimal dosage and the maximal tolerated dose (MTD) of topotecan and vinorelbine in patients with relapsed or refractory non-small cell or small cell lung cancer administered on an alternate dosing schedule. Methods From February, 2004 to March, 2007 eighteen patients with advanced or recurrent NSCLC or SCLC previously treated with chemotherapy were enrolled. Patients were heavily pretreated with 22% having received at least 3 prior lines of chemotherapy. Vinorelbine was administered at a fixed dose (20 mg/m2) and topotecan at escalating doses (2, 2.5, 3, 3.5, and 4 mg/m2) on days 1 and 8 every 21 days. Results The MTD was not reached in any of the 5 cohorts, with only one dose limiting toxicity (DLT) occurring in cohort 4. Non-hematological toxicities were manageable. One patient had a partial response with four patients (27%) achieving stable disease. The median progression-free and overall survival for all patients, were 2.7 months (95% CI: 1.6, 9.1) and 10.5 months (95% CI: 4.2, 22.7), respectively. Conclusion Vinorelbine and topotecan administered on days 1 and 8 every 21 days is well tolerated without any DLT seen with previously investigated topotecan schedules. This doublet provides a potentially active non-platinum containing doublet for the treatment of patients with advanced SCLC and NSCLC. Vinorelbine and topotecan should therefore be investigated in subsequent phase II studies at a dose of 20 mg/m2 and 4 mg/m2, respectively. Trial Registration Number NCT00287963.

Abstract Background COX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-κB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors. Methods Patients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days) or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days), in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily. Results No dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease. Conclusion The combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated. Trial registration number NCT00290680.

Abstract Background Speech perception is based on a variety of spectral and temporal acoustic features available in the acoustic signal. Voice-onset time (VOT) is considered an important cue that is cardinal for phonetic perception. Methods In the present study, we recorded and compared scalp auditory evoked potentials (AEP) in response to consonant-vowel-syllables (CV) with varying voice-onset-times (VOT) and non-speech analogues with varying noise-onset-time (NOT). In particular, we aimed to investigate the spatio-temporal pattern of acoustic feature processing underlying elemental speech perception and relate this temporal processing mechanism to specific activations of the auditory cortex. Results Results show that the characteristic AEP waveform in response to consonant-vowel-syllables is on a par with those of non-speech sounds with analogue temporal characteristics. The amplitude of the N1a and N1b component of the auditory evoked potentials significantly correlated with the duration of the VOT in CV and likewise, with the duration of the NOT in non-speech sounds. Furthermore, current density maps indicate overlapping supratemporal networks involved in the perception of both speech and non-speech sounds with a bilateral activation pattern during the N1a time window and leftward asymmetry during the N1b time window. Elaborate regional statistical analysis of the activation over the middle and posterior portion of the supratemporal plane (STP) revealed strong left lateralized responses over the middle STP for both the N1a and N1b component, and a functional leftward asymmetry over the posterior STP for the N1b component. Conclusion The present data demonstrate overlapping spatio-temporal brain responses during the perception of temporal acoustic cues in both speech and non-speech sounds. Source estimation evidences a preponderant role of the left middle and posterior auditory cortex in speech and non-speech discrimination based on temporal features. Therefore, in congruency with recent fMRI studies, we suggest that similar mechanisms underlie the perception of linguistically different but acoustically equivalent auditory events on the level of basic auditory analysis.

Abstract Spontaneous clearance of hepatitis C virus (HCV) has frequently been associated with the presence of HCV-specific cellular immunity. However, there had been also reports in chimpanzees demonstrating clearance of HCV-viremia in the absence of significant levels of detectable HCV-specific cellular immune responses. We here report seven asymptomatic acute hepatitis C cases with peak HCV-RNA levels between 300 and 100.000 copies/ml who all cleared HCV-RNA spontaneously. Patients were identified by a systematic screening of 1176 consecutive new incoming offenders in a German young offender institution. Four of the seven patients never developed anti-HCV antibodies and had normal ALT levels throughout follow-up. Transient weak HCV-specific CD4+ T cell responses were detectable in five individuals which did not differ in strength and breadth from age- and sex-matched patients with chronic hepatitis C and long-term recovered patients. In contrast, HCV-specific MHC-class-I-tetramer-positive cells were found in 3 of 4 HLA-A2-positive patients. Thus, these cases highlight that clearance of low levels of HCV viremia is possible in the absence of a strong adaptive immune response which might explain the low seroconversion rate after occupational exposure to HCV.

Abstract Background Recent findings of a tight coupling between visual and auditory association cortices during multisensory perception in monkeys and humans raise the question whether consistent paired presentation of simple visual and auditory stimuli prompts conditioned responses in unimodal auditory regions or multimodal association cortex once visual stimuli are presented in isolation in a post-conditioning run. To address this issue fifteen healthy participants partook in a "silent" sparse temporal event-related fMRI study. In the first (visual control) habituation phase they were presented with briefly red flashing visual stimuli. In the second (auditory control) habituation phase they heard brief telephone ringing. In the third (conditioning) phase we coincidently presented the visual stimulus (CS) paired with the auditory stimulus (UCS). In the fourth phase participants either viewed flashes paired with the auditory stimulus (maintenance, CS-) or viewed the visual stimulus in isolation (extinction, CS+) according to a 5:10 partial reinforcement schedule. The participants had no other task than attending to the stimuli and indicating the end of each trial by pressing a button. Results During unpaired visual presentations (preceding and following the paired presentation) we observed significant brain responses beyond primary visual cortex in the bilateral posterior auditory association cortex (planum temporale, planum parietale) and in the right superior temporal sulcus whereas the primary auditory regions were not involved. By contrast, the activity in auditory core regions was markedly larger when participants were presented with auditory stimuli. Conclusion These results demonstrate involvement of multisensory and auditory association areas in perception of unimodal visual stimulation which may reflect the instantaneous forming of multisensory associations and cannot be attributed to sensation of an auditory event. More importantly, we are able to show that brain responses in multisensory cortices do not necessarily emerge from associative learning but even occur spontaneously to simple visual stimulation.

Abstract Background Laser microdissection allows precise isolation of specific cell types and compartments from complex tissues. To analyse proteins from small cell numbers, we combine laser-microdissection and manipulation (LMM) with mass spectrometry techniques. Results Hemalaun stained mouse lung sections were used to isolate 500–2,000 cells, enough material for complex protein profiles by SELDI-TOF MS (surface enhanced laser desorption and ionization/time of flight mass spectrometry), employing different chromatographic ProteinChip® Arrays. Initially, to establish the principle, we identified specific protein peaks from 20,000 laser-microdissected cells, combining column chromatography, SDS-PAGE, tryptic digestion, SELDI technology and Tandem MS/MS using a ProteinChip® Tandem MS Interface. Secondly, our aim was to reduce the labour requirements of microdissecting several thousand cells. Therefore, we first defined target proteins in a few microdissected cells, then recovered in whole tissue section homogenates from the same lung and applied to these analytical techniques. Both approaches resulted in a successful identification of the selected peaks. Conclusion Laser-microdissection may thus be combined with SELDI-TOF MS for generation of protein marker profiles in a cell-type- or compartment-specific manner in complex tissues, linked with mass fingerprinting and peptide sequencing by Tandem MS/MS for definite characterization.

Abstract Background The time required for radiographic union following femoral fracture increases with age in both humans and rats for unknown reasons. Since abnormalities in fracture innervation will slow skeletal healing, we explored whether abnormal mRNA expression of genes related to nerve cell activity in the older rats was associated with the slowing of skeletal repair. Methods Simple, transverse, mid-shaft, femoral fractures with intramedullary rod fixation were induced in anaesthetized female Sprague-Dawley rats at 6, 26, and 52 weeks of age. At 0, 0.4, 1, 2, 4, and 6 weeks after fracture, a bony segment, one-third the length of the femur, centered on the fracture site, including the external callus, cortical bone, and marrow elements, was harvested. cRNA was prepared and hybridized to 54 Affymetrix U34A microarrays (3/age/time point). Results The mRNA levels of 62 genes related to neural function were affected by fracture. Of the total, 38 genes were altered by fracture to a similar extent at the three ages. In contrast, eight neural genes showed prolonged down-regulation in the older rats compared to the more rapid return to pre-fracture levels in younger rats. Seven genes were up-regulated by fracture more in the younger rats than in the older rats, while nine genes were up-regulated more in the older rats than in the younger. Conclusions mRNA of 24 nerve-related genes responded differently to fracture in older rats compared to young rats. This differential expression may reflect altered cell function at the fracture site that may be causally related to the slowing of fracture healing with age or may be an effect of the delayed healing.

Abstract Background Fracture healing slows with age. While 6-week-old rats regain normal bone biomechanics at 4 weeks after fracture, one-year-old rats require more than 26 weeks. The possible role of altered mRNA gene expression in this delayed union was studied. Closed mid-shaft femoral fractures were induced followed by euthanasia at 0 time (unfractured) or at 1, 2, 4 or 6 weeks after fracture in 6-week-old and 12-15-month-old Sprague-Dawley female rats. mRNA levels were measured for osteocalcin, type I collagen α1, type II collagen, bone morphogenetic protein (BMP)-2, BMP-4 and the type IA BMP receptor. Results For all of the genes studied, the mRNA levels increased in both age groups to a peak at one to two weeks after fracture. All gene expression levels decreased to very low or undetectable levels at four and six weeks after fracture for both age groups. At four weeks after fracture, the younger rats were healed radiographically, but not the older rats. Conclusions (1) All genes studied were up-regulated by fracture in both age groups. Thus, the failure of the older rats to heal promptly was not due to the lack of expression of any of the studied genes. (2) The return of the mRNA gene expression to baseline values in the older rats prior to healing may contribute to their delayed union. (3) No genes were overly up-regulated in the older rats. The slower healing response of the older rats did not stimulate a negative-feedback increase in the mRNA expression of stimulatory cytokines.

Purpose: The illicit injection of xylazine has recently been designated as an emerging public health threat. The use of this drug is associated with devastating soft-tissue necrosis that may lead to limb amputation. This study aimed to (1) report cases of soft-tissue injury from xylazine and (2) describe a staging and management algorithm for wounds related to xylazine use., Methods: A retrospective review was conducted to identify patients treated for xylazine-related soft-tissue necrosis at a trauma center. Clinical cases, treatment strategy, and available outcomes were presented. In addition, a comprehensive literature search was conducted using the keywords "xylazine" and "soft tissue.", Results: The management of seven patients with xylazine-related upper extremity soft-tissue necrosis was included, in addition to summarizing findings of five studies reporting on 13 additional cases. These cases were managed with local wound care (2 patients), soft-tissue reconstruction (4 patient), osseous reconstruction (1 patient), and limb amputation (10 patients)., Discussion: Acute treatment of xylazine-related soft-tissue necrosis is ideal to minimize morbidity and prevent limb loss. Management strategies of these wounds should be based on the depth of tissue involvement. Superficial ulceration involving the skin and subcutaneous tissue (Stage 1) should be managed with local wound care. Deeper ulceration involving tendons and/or muscle (Stage 2) requires surgical débridement and soft-tissue reconstruction. Deeper ulceration involving bone (Stage 3) requires osseous débridement and reconstruction. Finally, when all tissues in the extremity are involved (Stage 4), amputation is often necessary., (Copyright © 2024 by the American Academy of Orthopaedic Surgeons.)

Immune related adverse events (irAEs) after immune checkpoint blockade (ICB) therapy occur in a significant proportion of cancer patients. To date, the circulating mediators of ICB-irAEs remain poorly understood. Using non-targeted mass spectrometry, here we identify the circulating bio-active lipid linoleoyl-lysophosphatidylcholine (LPC 18:2) as a modulator of ICB-irAEs. In three independent human studies of ICB treatment for solid tumor, loss of circulating LPC 18:2 preceded the development of severe irAEs across multiple organ systems. In both healthy humans and severe ICB-irAE patients, low LPC 18:2 was found to correlate with high blood neutrophilia. Reduced LPC 18:2 biosynthesis was confirmed in preclinical ICB-irAE models, and LPC 18:2 supplementation in vivo suppressed neutrophilia and tissue inflammation without impacting ICB anti-tumor response. Results indicate that circulating LPC 18:2 suppresses human ICB-irAEs, and LPC 18:2 supplementation may improve ICB outcomes by preventing severe inflammation while maintaining anti-tumor immunity.

Elbow stability arises from a combination of bony congruity, static ligamentous and capsular restraints, and dynamic muscular activation. Elbow trauma can disrupt these static and dynamic stabilizers leading to predictable patterns of instability; these patterns are dependent on the mechanism of injury and a progressive failure of anatomic structures. An algorithmic approach to the diagnosis and treatment of complex elbow fracture-dislocation injuries can improve the diagnostic assessment and reconstruction of the bony and ligamentous restraints to restore a stable and functional elbow. Achieving optimal outcomes requires a comprehensive understanding of pertinent local and regional anatomy, the altered mechanics associated with elbow injury, versatility in surgical approaches and fixation methods, and a strategic rehabilitation plan., (Copyright © 2024 by the American Academy of Orthopaedic Surgeons.)

Background: Forest disturbances are projected to increase in intensity and frequency in the upcoming decades. The projected change in disturbance regimes is expected to alter the provision of ecosystem services and affect biodiversity. Both are critical for forest ecosystems to provide livelihoods for human societies. Forest management after natural disturbances shapes successional pathways of forest ecosystems. Therefore, the management of post-disturbance sites deserves critical attention to avoid negative effects of management interventions on ecosystem services and biodiversity. The two most common management interventions after natural disturbances are salvage logging (comparator: no salvage logging) and tree planting (comparator: natural regeneration). This planned systematic map of reviews aims to aggregate the existing evidence syntheses on the implications of common forest management interventions after natural disturbances on successional trajectories with regard to selected ecosystem services and biodiversity. Evidence-based post-disturbance management is highly relevant for protected area management as well as for the management of commercial forests., Methods: We will systematically search the databases Scopus, Web of Science Core Collection and the Forest Science Collection of the CABI Digital Library for reviews and meta-analyses (after 2003). We will apply eligibility criteria for review selection and assess the evidence synthesis validity of selected reviews using the most recent version of CEESAT (Collaboration for Environmental Evidence Synthesis Assessment Tool). The results will be displayed in topic subgroups in summary of scope and summary of findings tables., (© 2024. The Author(s).)

Purpose: This study aimed to quantify the impact of pre-existing psychiatric illness on inpatient outcomes after major trauma and to assess acuity of psychiatric presentation as a predictor of outcomes., Methods: A retrospective single-center cohort study identified adult trauma patients with an Injury Severity Score (ISS) ≥ 16 between January 2018 and December 2019. Bivariate analysis assessed patient characteristics, injury characteristics, and injury outcomes between patients with and without psychiatric comorbidity. A sub-group analysis explored further effects of psychiatric history and need for inpatient psychiatric consultation on outcomes., Results: Of 640 patients meeting inclusion criteria, 99 patients (15.4%) had at least one psychiatric comorbidity. Patients with psychiatric comorbidity sustained distinct mechanisms of injury and higher in-hospital morbidity (44% vs. 26%, OR 1.97, 95% CI 1.17-3.3, p = 0.01), including pulmonary morbidity (31% vs. 21%, p < 0.01), neurologic morbidity (18% vs 7%, p < 0.01), and deep wound infection (8% vs. 2%, p < 0.01) than the control cohort. Psychiatric patients also had significantly greater median intensive care unit (ICU), length of stay (LOS) (1 day vs. 0 days, p = 0.04), median inpatient ward LOS (10 days vs. 7 days, p = 0.02), and median overall hospital LOS (16 days vs. 11 days, p < 0.01). In sub-group analysis, patients with a history of psychiatric illness alone had comparable outcomes to the control group., Conclusions: Psychiatric comorbidity negatively impacts inpatient morbidity and inpatient LOS. This effect is most pronounced among acute psychiatric episodes with or without a history of mental illness., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Ulnar styloid fractures commonly occur in the setting of distal radius fractures and often progress to asymptomatic nonunion. Displaced basilar ulnar styloid fractures involving the deep radioulnar ligament attachments may cause distal radioulnar joint (DRUJ) instability. A careful clinical history, physical examination, review of imaging studies, and selected diagnostic interventions are important for confirming the relationship of the ulnar styloid nonunion with ulnar-sided wrist symptoms and/or DRUJ instability. Improved functional and symptomatic outcomes can be achieved with nonunion repair or fragment excision with or without triangular fibrocartilage complex repair, depending on the location and size of the ulnar styloid fracture., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This study provides evidence of fine-grained genetic structuring in Mediterranean mussels (Mytilus galloprovincialis) from the Strait of Istanbul, caused by barriers to gene flow via contaminant-mediated selection. In this study, mitochondrial D-loop sequences were analyzed in mussels from 8 localities, all less than 30 kilometers apart, with differing contaminant loads. The results were: 1) Intra-population genetic differentiation (Φ ST ) between sites with high and low contaminant loads was high (up to 0.459), even at distances of only a few kilometers. 2) Genetic diversity was negatively correlated with the contaminant load ("genetic erosion"). 3) There was evidence of selection, based on haplotype frequencies and neutrality tests (Tajima's D), with purifying selection at the most contaminated site and balancing selection at the least contaminated. 4) Genetic distance was not correlated with geographic distance (no isolation-by-distance), but was correlated with contaminant load at each site. 5) Population dendrograms and Bayesian estimators of migration indicated that gene flow between sites was affected by contamination. For the dendrograms of the sampling sites, the clades clustered according to contaminant load more than geographic distance. Overall, these results suggest that 1) contamination may serve as a genotype-dependent dispersal barrier (i.e., contamination may not affect total number of migrants, just the relative proportions of the haplotypes in the established immigrants), leading strong population differentiation over short distances, and 2) genetic erosion may occur by a combination of selection and altered patterns of haplotype-specific gene flow. These effects may be more pronounced in the Strait of Istanbul than in other locations because of the riverine nature and strong, uni-directional current of the strait., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Flooding events are the most common natural hazard globally, resulting in vast destruction and loss of life. An effective flood emergency response is necessary to lessen the negative impacts of flood disasters. However, disaster management and response efforts face a complex scenario. Simultaneously, regular citizens attempt to navigate the various sources of information being distributed and determine their best course of action. One thing is evident across all disaster scenarios: having accurate information and clear communication between citizens and rescue personnel is critical. This research aims to identify the diverse needs of two groups, rescue operators and citizens, during flood disaster events by investigating the sources and types of information they rely on and information that would improve their responses in the future. This information can improve the design and implementation of existing and future spatial decision support systems (SDSSs) during flooding events. This research identifies information characteristics crucial for rescue operators and everyday citizens' response and possible evacuation to flooding events by qualitatively coding survey responses from rescue responders and the public. The results show that including local input in SDSS development is crucial for improving higher-resolution flood risk quantification models. Doing so democratizes data collection and analysis, creates transparency and trust between people and governments, and leads to transformative solutions for the broader scientific community.

Purpose: Due to their abundance in the blood, low RNA content, and short lifespan, neutrophils have been classically considered to be one homogenous pool. However, recent work has found that mature neutrophils and neutrophil progenitors are composed of unique subsets exhibiting context-dependent functions. In this study, we ask if neutrophil heterogeneity is associated with melanoma incidence and/or disease stage., Experimental Design: Using mass cytometry, we profiled melanoma patient blood for unique cell surface markers among neutrophils. Markers were tested for their predictiveness using flow cytometry data and random forest machine learning., Results: We identified CD79b + neutrophils (CD3 - CD56 - CD19 - Siglec8 - CD203c - CD86 Lo CD66b + CD79b + ) that are normally restricted to the bone marrow in healthy humans but appear in the blood of subjects with early-stage melanoma. Further, we found CD79b + neutrophils present in tumors of subjects with head and neck cancer. AI-mediated machine learning analysis of neutrophils from subjects with melanoma confirmed that CD79b expression among peripheral blood neutrophils is highly important in identifying melanoma incidence. We noted that CD79b + neutrophils possessed a neutrophilic appearance but have transcriptional and surface-marker phenotypes reminiscent of B cells. Compared to remaining blood neutrophils, CD79b + neutrophils are primed for NETosis, express higher levels of antigen presentation-related proteins, and have an increased capacity for phagocytosis., Conclusion: Our work suggests that CD79b + neutrophils are associated with early-stage melanoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AR declared a shared affiliation with the authors YZ and CO to the handling editor at the time of review., (Copyright © 2023 Meyer, Dinh, Alimadadi, Araujo, Chatterjee, Gutierrez, Zhu, Hunter, Liang, Seumois, Kiosses, Catz, Vijayanand, Ottensmeier and Hedrick.)

Purpose: The purpose of this study was to assess the impact of resident involvement on periprocedural outcomes and costs after common procedures performed at an academic hand surgical practice., Methods: A retrospective review was performed in all patients undergoing 7 common elective upper extremity procedures between January 2008 and December 2018: carpal tunnel release, distal radius open reduction and internal fixation (ORIF), trigger finger release, thumb carpometacarpal arthroplasty, phalanx closed reduction and percutaneous pinning, cubital tunnel release, and olecranon ORIF. The medical record was reviewed to determine the impact of surgical assistants (resident, fellow, or physician assistant) on periprocedural outcomes, periprocedural costs, and 1-year postoperative outcomes. The involvement of surgical trainees operating under direct supervision was compared with the entire operation performed by the attending surgeon with a physician assistant present., Results: A total of 396 procedures met the inclusion criteria. Analysis of the whole study sample revealed low rates of intraoperative complications, wound complications, medical complications, readmissions, and mortality. Subgroup analysis of carpal tunnel releases revealed significantly greater tourniquet times for residents compared with physician assistants (7 ± 2 min, 6 ± 1 min), as well as longer overall operating room times for residents compared to fellows or physician assistants (17 ± 5 min, 13 ± 3 min, 12 ± 3 min). Operating room times for distal radius ORIF were significantly greater among residents compared to fellows or physician assistants (68 ± 19 min, 57 ± 17 min, 56 ± 14 min). There were no differences in any other perioperative metrics or periprocedural costs for the trigger finger release or cubital tunnel release cohorts., Conclusions: Resident involvement in select upper extremity procedures can lengthen operative times but does not have an impact on blood loss or operating room costs., Clinical Relevance: Surgeons should be aware that having a resident assistant slightly increases operative times in elective hand surgery., (Copyright © 2023. Published by Elsevier Inc.)

Importance: Increased cancer risk in first-degree relatives of probands with pancreatic ductal adenocarcinoma (PDAC probands) who carry pathogenic or likely pathogenic germline variants (PGVs) in cancer syndrome-associated genes encourages cascade genetic testing. To date, unbiased risk estimates for the development of cancers on a gene-specific basis have not been assessed., Objective: To quantify the risk of development of PDAC and extra-PDAC among first-degree relatives of PDAC probands who carry a PGV in 1 of 9 cancer syndrome-associated genes-ATM, BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2, and CDKN2A., Design, Setting, and Participants: This case series focused on first-degree relatives of PDAC probands carrying PGVs in specific cancer syndrome-associated genes. The cohort comprised clinic-ascertained patients enrolled in the Mayo Clinic Biospecimen Resource for Pancreas Research registry with germline genetic testing. In total, 234 PDAC probands carrying PGVs were drawn from the prospective research registry of 4562 participants who had undergone genetic testing of cancer syndrome-associated genes. Demographic and cancer-related family histories were obtained by questionnaire. The data were collected from October 1, 2000, to December 31, 2021., Main Outcomes and Measures: For the PDAC probands, the genetic test results of the presence of PGVs in 9 cancer syndrome-associated genes were obtained by clinical testing. Cancers (ovary, breast, uterus or endometrial, colon, malignant melanoma, and pancreas) among first-degree relatives were reported by the probands. Standardized incidence ratios (SIRs) were used to estimate cancer risks among first-degree relatives of PDAC probands carrying a PGV., Results: In total, 1670 first-degree relatives (mean [SD] age, 58.1 [17.8] years; 853 male [51.1%]) of 234 PDAC probands (mean [SD] age, 62.5 [10.1] years; 124 male [53.0%]; 219 [94.4%] White; 225 [98.7%] non-Hispanic or non-Latino]) were included in the study. There was a significantly increased risk of ovarian cancer in female first-degree relatives of probands who had variants in BRCA1 (SIR, 9.49; 95% CI, 3.06-22.14) and BRCA2 (SIR, 3.72; 95% CI, 1.36-8.11). Breast cancer risks were higher with BRCA2 variants (SIR, 2.62; 95% CI, 1.89-3.54). The risks of uterine or endometrial cancer (SIR, 6.53; 95% CI, 2.81-12.86) and colon cancer (SIR, 5.83; 95% CI, 3.70-8.75) were increased in first-degree relatives of probands who carried Lynch syndrome mismatch repair variants. Risk of PDAC was also increased for variants in ATM (SIR, 4.53; 95% CI, 2.69-7.16), BRCA2 (SIR, 3.45; 95% CI, 1.72-6.17), CDKN2A (SIR, 7.38; 95% CI, 3.18-14.54), and PALB2 (SIR, 5.39; 95% CI, 1.45-13.79). Melanoma risk was elevated for first-degree relatives of probands with CDKN2A variants (SIR, 7.47; 95% CI, 3.97-12.77)., Conclusions and Relevance: In this case series, the presence of PGVs in 9 cancer syndrome-associated genes in PDAC probands was found to be associated with increased risk of 6 types of cancers in first-degree relatives. These gene-specific PDAC and extra-PDAC cancer risks may provide justification for clinicians to counsel first-degree relatives about the relevance and importance of genetic cascade testing, with the goal of higher uptake of testing.